rs34162630

Variant names:

• chrX-49226037-C-G
• rs34162630
• NM_001256789.3:c.1523G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-49226037-C-G
• chrX-49226037-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001256789.3(CACNA1F):​c.1523G>C​(p.Arg508Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000928 in 1,077,581 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R508Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

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]

CACNA1F Gene-Disease associations (from GenCC):

• Aland island eye disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• inherited retinal dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness 2A

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• X-linked cone-rod dystrophy 3

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.1523G>C	p.Arg508Pro	missense_variant	Exon 13 of 48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.1556G>C	p.Arg519Pro	missense_variant	Exon 13 of 48		NP_005174.2
CACNA1F	NM_001256790.3	c.1361G>C	p.Arg454Pro	missense_variant	Exon 13 of 48		NP_001243719.1
CACNA1F	XM_011543983.3	c.1361G>C	p.Arg454Pro	missense_variant	Exon 13 of 47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.1523G>C	p.Arg508Pro	missense_variant	Exon 13 of 48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.1556G>C	p.Arg519Pro	missense_variant	Exon 13 of 48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.1361G>C	p.Arg454Pro	missense_variant	Exon 13 of 48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.28e-7 AC: 1 AN: 1077581 Hom.: 0 Cov.: 32 AF XY: 0.00000285 AC XY: 1 AN XY: 351207

African (AFR) AF: 0.00 AC: 0 AN: 25886

American (AMR) AF: 0.00 AC: 0 AN: 32117

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19020

East Asian (EAS) AF: 0.00 AC: 0 AN: 29016

South Asian (SAS) AF: 0.00 AC: 0 AN: 51616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39117

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4115

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 831372

Other (OTH) AF: 0.00 AC: 0 AN: 45322

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;.;M
PhyloP100		7.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.4	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.88
MutPred		0.73		.;.;Loss of methylation at R519 (P = 0.0398);
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.96
gMVP		0.96
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34162630; hg19: chrX-49082499;