X-49205189-C-T

Position:

• chrX-49205189-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001256789.3(CACNA1F):​c.5849G>A​(p.Arg1950His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,097,076 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0940

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11218697).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.5849G>A	p.Arg1950His	missense_variant	48/48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.5849G>A	p.Arg1950His	missense_variant	48/48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.5882G>A	p.Arg1961His	missense_variant	48/48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.5687G>A	p.Arg1896His	missense_variant	48/48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 182143 Hom.: 0 AF XY: 0.0000150 AC XY: 1 AN XY: 66827

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1097076 Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 3 AN XY: 362496

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 13, 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 histidine 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: 855148). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1961 of the CACNA1F protein (p.Arg1961His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.3
DANN	Benign	0.71
DEOGEN2	Benign	0.19	.;.;T
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.90	.;.;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.0080	.;.;B
Vest4		0.11
MutPred		0.39		.;.;Gain of sheet (P = 0.0507);
MVP		0.48
MPC		0.30
ClinPred		0.015	T
GERP RS		2.3
Varity_R		0.050
gMVP		0.66

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: rs782337448; hg19: chrX-49061649; COSMIC: COSV54294494; COSMIC: COSV54294494;