X-49205282-C-T

Variant summary

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

The NM_001256789.3(CACNA1F):c.5756G>A(p.Arg1919His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,206,688 control chromosomes in the GnomAD database, including 3,568 homozygotes. There are 36,726 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1919R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.067 (252 hom., 2164 hem., cov: 22)
  • Exomes 𝑓: 0.090 (3316 hom. 34562 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.47

Genes affected

CACNA1F (HGNC:1393): (calcium voltage-gated channel subunit alpha1 F) This gene encodes a multipass transmembrane protein that functions as an alpha-1 subunit of the voltage-dependent calcium channel, which mediates the influx of calcium ions into the cell. The encoded protein forms a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Mutations in this gene can cause X-linked eye disorders, including congenital stationary night blindness type 2A, cone-rod dystropy, and Aland Island eye disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017129481).
• BP6: Variant X-49205282-C-T is Benign according to our data. Variant chrX-49205282-C-T is described in ClinVar as [Benign]. Clinvar id is 100576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49205282-C-T is described in Lovd as [Benign]. Variant chrX-49205282-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1F	NM_001256789.3	c.5756G>A	p.Arg1919His	missense_variant	48/48	ENST00000323022.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1F	ENST00000323022.10	c.5756G>A	p.Arg1919His	missense_variant	48/48	1	NM_001256789.3
CACNA1F	ENST00000376265.2	c.5789G>A	p.Arg1930His	missense_variant	48/48	1		P1
CACNA1F	ENST00000376251.5	c.5594G>A	p.Arg1865His	missense_variant	48/48	1

Frequencies

GnomAD3 genomes AF: 0.0668 AC: 7369 AN: 110233 Hom.: 252 Cov.: 22 AF XY: 0.0665 AC XY: 2162 AN XY: 32515

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00590

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.0782

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.0297

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0660

GnomAD3 exomes AF: 0.0979 AC: 17653 AN: 180387 Hom.: 640 AF XY: 0.105 AC XY: 6860 AN XY: 65277

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.0680

Gnomad ASJ exome AF: 0.0761

Gnomad EAS exome AF: 0.188

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.0826

Gnomad NFE exome AF: 0.0811

Gnomad OTH exome AF: 0.0843

GnomAD4 exome AF: 0.0903 AC: 99025 AN: 1096402 Hom.: 3316 Cov.: 31 AF XY: 0.0955 AC XY: 34562 AN XY: 361860

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.0659

Gnomad4 ASJ exome AF: 0.0754

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.0831

Gnomad4 NFE exome AF: 0.0824

Gnomad4 OTH exome AF: 0.0897

GnomAD4 genome AF: 0.0668 AC: 7362 AN: 110286 Hom.: 252 Cov.: 22 AF XY: 0.0664 AC XY: 2164 AN XY: 32578

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.0540

Gnomad4 ASJ AF: 0.0782

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.0744

Gnomad4 NFE AF: 0.0801

Gnomad4 OTH AF: 0.0651

Alfa AF: 0.0794 Hom.: 4376

Bravo AF: 0.0614

TwinsUK AF: 0.0790 AC: 293

ALSPAC AF: 0.0848 AC: 245

ESP6500AA AF: 0.0214 AC: 82

ESP6500EA AF: 0.0846 AC: 569

ExAC AF: 0.103 AC: 12483

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2018	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. -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	10
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.23	N;N;N
REVEL	Benign	0.051
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.031
MPC		0.28
ClinPred		0.013	T
GERP RS		1.1
Varity_R		0.044
gMVP		0.65

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: rs33910054; hg19: chrX-49061742; COSMIC: COSV59904636; COSMIC: COSV59904636;