3-53800340-G-A

Position:

• chr3-53800340-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS1_Supporting

The NM_001128840.3(CACNA1D):​c.5015G>A​(p.Arg1672Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,459,578 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (1 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.60

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]

CACNA1D (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 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=0.059493244).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000026 (38/1459578) while in subpopulation MID AF= 0.00295 (17/5766). AF 95% confidence interval is 0.00188. There are 1 homozygotes in gnomad4_exome. There are 17 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.5075G>A	p.Arg1692Gln	missense_variant	42/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.5015G>A	p.Arg1672Gln	missense_variant	41/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.5075G>A	p.Arg1692Gln	missense_variant	42/49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.5015G>A	p.Arg1672Gln	missense_variant	41/48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251486 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1459578 Hom.: 1 Cov.: 29 AF XY: 0.0000234 AC XY: 17 AN XY: 726322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000901

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 504808). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. This variant is present in population databases (rs148898845, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1692 of the CACNA1D protein (p.Arg1692Gln). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 21, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Arg1692Gln va riant in CACNA1D has not been previously reported in individuals with hearing lo ss, but has been identified in 1/16512 South Asian chromosomes and 1/11576 Latin o chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs148898845). Arginine (Arg) at position 1692 is not conserved in mammals or evolutionarily distant species and 2 mammals (opossum and Tasmanian devil) carry a glutamine (Gln) at this position, supporting that this change may be tolerated. In summary, while the clinical significance of the p.Arg1692Gln variant is uncertain, these data suggest that it is more likely to be benign. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The c.5075G>A (p.R1692Q) alteration is located in exon 42 (coding exon 42) of the CACNA1D gene. This alteration results from a G to A substitution at nucleotide position 5075, causing the arginine (R) at amino acid position 1692 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.075	.;T;.;.;.;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.87	D;D;.;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.059	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	-0.69	.;N;.;.;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.48	.;N;.;N;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.40	.;T;.;T;T;.;T
Sift4G	Benign	0.58	.;T;.;T;T;.;T
Polyphen		0.0010, 0.029	.;B;B;B;.;.;B
Vest4		0.18, 0.18, 0.19
MVP		0.55
MPC		0.43
ClinPred		0.054	T
GERP RS		-0.096
Varity_R		0.039
gMVP		0.43

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: rs148898845; hg19: chr3-53834367; COSMIC: COSV55458946; COSMIC: COSV55458946;