rs398122827

chr3-53673802-T-TGGG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_000720.4(CACNA1D):c.1208_1209insGGG(p.Gly403_Val403insGly) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1D NM_000720.4 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S6 of repeat I (size 24) in uniprot entity CAC1D_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000720.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000720.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-53673802-T-TGGG is Pathogenic according to our data. Variant chr3-53673802-T-TGGG is described in ClinVar as [Pathogenic]. Clinvar id is 39709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.1208_1209insGGG	p.Gly403_Val403insGly	inframe_insertion	8/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.1220+678_1220+679insGGG		intron_variant		ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1208_1209insGGG	p.Gly403_Val403insGly	inframe_insertion	8/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.1220+678_1220+679insGGG		intron_variant		1	NM_001128840.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251492 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000205 AC: 3 AN: 1460284 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sinoatrial node dysfunction and deafness Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The variant c.1208_1209insGGG (p.Gly403dup) in CACNA1D gene has been reported previously in patients affected with sinoatrial node dysfunction and deafness that segregated with disease in the family (Baig et al., 2011). This variant has been reported to the ClinVar database as Pathogenic. The p.Gly403dup variant is reported with the allele frequency (0.0007%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This p.Gly403dup causes duplication of amino acid Glycine at postion 403. Alleles of single nucleotide polymorphisms (SNPs) from the CACNA1D locus have revealed the same c.1208_1209insGGG associated haplotype in three families, compatible with a founder mutation inherited from a common ancestor (Baig et al., 2011). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 25, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39709). This variant is also known as p.403_404insGly. This variant has been observed in individual(s) with autosomal recessive sinoatrial node dysfunction and deafness (PMID: 21131953, 30498240). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs751923238, gnomAD 0.006%). This variant, c.1208_1209insGGG, results in the insertion of 1 amino acid(s) of the CACNA1D protein (p.Gly403dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122827; hg19: chr3-53707829;