3-53494986-T-TA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000720.4(CACNA1D):c.-178dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 400,616 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 27)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: CACNA1D NM_000720.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.17

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.

• BP6: Variant 3-53494986-T-TA is Benign according to our data. Variant chr3-53494986-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 1206457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0051 (769/150674) while in subpopulation AFR AF= 0.0171 (704/41050). AF 95% confidence interval is 0.0161. There are 4 homozygotes in gnomad4. There are 365 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.-178dup		5_prime_UTR_variant	1/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.-178dup		5_prime_UTR_variant	1/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.-178dup		5_prime_UTR_variant	1/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.-178dup		5_prime_UTR_variant	1/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 767 AN: 150576 Hom.: 4 Cov.: 27

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.00387

GnomAD4 exome AF: 0.00141 AC: 353 AN: 249942 Hom.: 2 Cov.: 4 AF XY: 0.00135 AC XY: 182 AN XY: 134940

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.000926

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.000770

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.000945

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00510 AC: 769 AN: 150674 Hom.: 4 Cov.: 27 AF XY: 0.00497 AC XY: 365 AN XY: 73486

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000413

Gnomad4 OTH AF: 0.00383

Alfa AF: 0.00489 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2020

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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: rs112104996; hg19: chr3-53529013;