3-53753597-A-G

Position:

• chr3-53753597-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The ENST00000350061.11(CACNA1D):​c.3701A>G​(p.Asn1234Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000799 in 1,611,702 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1234I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (3 hom.)
• Consequence: CACNA1D ENST00000350061.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 7.57

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 Benign. Variant got -10 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1D. . Gene score misZ 4.5817 (greater than the threshold 3.09). Trascript score misZ 6.6073 (greater than threshold 3.09). GenCC has associacion of gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09306714).
• BP6: Variant 3-53753597-A-G is Benign according to our data. Variant chr3-53753597-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504807.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr3-53753597-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000433 (66/152348) while in subpopulation EAS AF= 0.00116 (6/5192). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.3761A>G	p.Asn1254Ser	missense_variant	30/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.3701A>G	p.Asn1234Ser	missense_variant	29/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.3761A>G	p.Asn1254Ser	missense_variant	30/49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.3701A>G	p.Asn1234Ser	missense_variant	29/48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000537 AC: 135 AN: 251494 Hom.: 1 AF XY: 0.000544 AC XY: 74 AN XY: 135922

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000837 AC: 1221 AN: 1459354 Hom.: 3 Cov.: 30 AF XY: 0.000843 AC XY: 612 AN XY: 726182

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.000534

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000910

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74504

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000590 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	- -

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 05, 2022	DNA sequence analysis of the CACNA1D gene demonstrated a sequence change, c.3761A>G, in exon 30 that results in an amino acid change, p.Asn1254Ser. This sequence change does not appear to have been previously described in individuals with CACNA1D-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.05% in the overall population (dbSNP rs147146258). The p.Asn1254Ser change affects a highly conserved amino acid residue located in a domain of the CACNA1D protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn1254Ser substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asn1254Ser change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 24, 2016	The p.Asn1254Ser variant in CACNA1D has not been previously reported in individu als with hearing loss, but has been identified in several populations by the Exo me Aggregation Consortium including 0.1% (39/66732) of European chromosomes (ExA C, http://exac.broadinstitute.org; dbSNP rs147146258). Although this variant has been seen in the general population, its frequency is not high enough to rule o ut a pathogenic role. Computational prediction tools and conservation analyses d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Asn1254Ser variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

The c.3761A>G (p.N1254S) alteration is located in exon 30 (coding exon 30) of the CACNA1D gene. This alteration results from a A to G substitution at nucleotide position 3761, causing the asparagine (N) at amino acid position 1254 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;D;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.71	.;N;.;.;.;N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	.;D;.;.;D;D;.;.;D;.;.
REVEL	Uncertain	0.47
Sift	Benign	0.18	.;T;.;.;T;T;.;.;T;.;.
Sift4G	Benign	0.37	.;T;.;.;T;T;.;.;T;.;.
Polyphen		0.13, 0.54, 0.89	.;B;.;P;P;.;.;.;P;.;.
Vest4		0.69, 0.68, 0.68
MVP		0.88
MPC		1.7
ClinPred		0.035	T
GERP RS		5.9
Varity_R		0.33
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147146258; hg19: chr3-53787624;