rs200382504

Variant names:

• chr3-53762032-C-T
• rs200382504
• NM_000720.4:c.3881C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_001128840.3(CACNA1D):​c.3821C>T​(p.Ser1274Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000331 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 3.94

Genes affected

CACNA1D (HGNC:1391): (calcium voltage-gated channel subunit alpha1 D) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in the CACNA1D gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. Gene score misZ: 4.5817 (above the threshold of 3.09). Trascript score misZ: 6.6073 (above the threshold of 3.09). GenCC associations: The gene is linked to sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.097922385).
• BP6: Variant 3-53762032-C-T is Benign according to our data. Variant chr3-53762032-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228465.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000184 (28/152214) while in subpopulation NFE AF= 0.000294 (20/68028). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.3881C>T	p.Ser1294Phe	missense_variant	Exon 31 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.3821C>T	p.Ser1274Phe	missense_variant	Exon 30 of 48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.3881C>T	p.Ser1294Phe	missense_variant	Exon 31 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.3821C>T	p.Ser1274Phe	missense_variant	Exon 30 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 251496 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000346 AC: 506 AN: 1461536 Hom.: 0 Cov.: 30 AF XY: 0.000359 AC XY: 261 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000386

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000709

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Dec 05, 2022

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser1294Phe variant in the CACNA1D gene has not been previously reported in association with disease. This variant has been identified in 36/129196 European Non-Finnish chromosomes (63/282888 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 228465). The CACNA1D gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ser1294Phe variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP2; PP3] -

Jun 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 01, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ser1294Phe va riant in CACNA1D has been previously reported by our laboratory in one individua l with an alternate genetic etiology to explain the hearing loss. This variant was identified in 16/66738 European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs200382504); however, this fre quency in the general population is not high enough to rule out a pathogenic rol e. Computational prediction tools and conservation analyses suggest that this va riant may not impact the protein, though this information is not predictive enou gh to rule out pathogenicity. In summary, while the clinical significance of the p.Ser1294Phe variant is uncertain, these data suggest that it is more likely to be benign. -

Inborn genetic diseases Uncertain:1

Mar 19, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3881C>T (p.S1294F) alteration is located in exon 31 (coding exon 31) of the CACNA1D gene. This alteration results from a C to T substitution at nucleotide position 3881, causing the serine (S) at amino acid position 1294 to be replaced by a phenylalanine (F). The in silico prediction for the p.S1294F alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CACNA1D-related disorder Benign:1

Jan 24, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Benign	0.31
DEOGEN2	Uncertain	0.53	.;D;.;.;.;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.090
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.098	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	-1.9	.;N;.;.;.;N;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.3	.;N;.;.;N;N;.;.
REVEL	Uncertain	0.51
Sift	Benign	1.0	.;T;.;.;T;T;.;.
Sift4G	Benign	1.0	.;T;.;.;T;T;.;.
Polyphen		0.0, 0.010	.;B;.;B;B;.;.;.
Vest4		0.52, 0.53, 0.53
MVP		0.88
MPC		1.6
ClinPred		0.083	T
GERP RS		5.4
Varity_R		0.16
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200382504; hg19: chr3-53796059; COSMIC: COSV55467947;