3-53673826-C-T

Variant names:

• chr3-53673826-C-T
• rs117630105
• NM_000720.4:c.1220+10C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128840.3(CACNA1D):​c.1220+700C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,571,500 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (152 hom.)
• Consequence: CACNA1D NM_001128840.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.77

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 3-53673826-C-T is Benign according to our data. Variant chr3-53673826-C-T is described in ClinVar as [Benign]. Clinvar id is 226468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53673826-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.1220+10C>T		intron_variant	Intron 8 of 48	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.1220+700C>T		intron_variant	Intron 8 of 47	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1220+10C>T		intron_variant	Intron 8 of 48	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.1220+700C>T		intron_variant	Intron 8 of 47	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 645 AN: 152164 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0847

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00963 AC: 2422 AN: 251482 Hom.: 78 AF XY: 0.0101 AC XY: 1374 AN XY: 135918

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.0899

Gnomad SAS exome AF: 0.0188

Gnomad FIN exome AF: 0.00420

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00385 AC: 5469 AN: 1419218 Hom.: 152 Cov.: 25 AF XY: 0.00426 AC XY: 3022 AN XY: 708860

Gnomad4 AFR exome AF: 0.000245

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.000851

Gnomad4 EAS exome AF: 0.0766

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.00386

Gnomad4 NFE exome AF: 0.000218

Gnomad4 OTH exome AF: 0.00659

GnomAD4 genome AF: 0.00421 AC: 641 AN: 152282 Hom.: 24 Cov.: 32 AF XY: 0.00485 AC XY: 361 AN XY: 74468

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0843

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000520 Hom.: 1

Bravo AF: 0.00414

Asia WGS AF: 0.0500 AC: 172 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1220+10C>T in intron 8 of CACNA1D: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 12.9% (25/194) of Han Chinese chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/pro jects/SNP; dbSNP rs117630105). -

Aldosterone-producing adenoma with seizures and neurological abnormalities Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.86

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: rs117630105; hg19: chr3-53707853; COSMIC: COSV55437865;