X-49223081-T-C

Variant names:

• chrX-49223081-T-C
• rs1344295491
• NM_001256789.3:c.1933A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001256789.3(CACNA1F):​c.1933A>G​(p.Ile645Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000583 in 1,200,838 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I645F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96
• 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)
• CACNA1F-related retinopathy

  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_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256789.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	NM_001256789.3	MANE Select	c.1933A>G	p.Ile645Val	missense	Exon 15 of 48	NP_001243718.1	O60840-2
	CACNA1F	NM_005183.4		c.1966A>G	p.Ile656Val	missense	Exon 15 of 48	NP_005174.2	O60840-1
	CACNA1F	NM_001256790.3		c.1771A>G	p.Ile591Val	missense	Exon 15 of 48	NP_001243719.1	O60840-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	ENST00000323022.10	TSL:1 MANE Select	c.1933A>G	p.Ile645Val	missense	Exon 15 of 48	ENSP00000321618.6	O60840-2
	CACNA1F	ENST00000376265.2	TSL:1	c.1966A>G	p.Ile656Val	missense	Exon 15 of 48	ENSP00000365441.2	O60840-1
	CACNA1F	ENST00000376251.5	TSL:1	c.1771A>G	p.Ile591Val	missense	Exon 15 of 48	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes AF: 0.00000904 AC: 1 AN: 110614 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 6 AN: 1090224 Hom.: 0 Cov.: 30 AF XY: 0.00000841 AC XY: 3 AN XY: 356530

African (AFR) AF: 0.0000380 AC: 1 AN: 26317

American (AMR) AF: 0.00 AC: 0 AN: 34408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19239

East Asian (EAS) AF: 0.00 AC: 0 AN: 30107

South Asian (SAS) AF: 0.0000190 AC: 1 AN: 52686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.00000478 AC: 4 AN: 837418

Other (OTH) AF: 0.00 AC: 0 AN: 45856

GnomAD4 genome AF: 0.00000904 AC: 1 AN: 110614 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32854

African (AFR) AF: 0.0000330 AC: 1 AN: 30334

American (AMR) AF: 0.00 AC: 0 AN: 10406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3502

South Asian (SAS) AF: 0.00 AC: 0 AN: 2595

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5869

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52868

Other (OTH) AF: 0.00 AC: 0 AN: 1484

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.91	N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.024	D
Polyphen		0.90	P
Vest4		0.44
MutPred		0.71		Loss of catalytic residue at L661 (P = 0.0747)
MVP		0.94
MPC		0.60
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.48
gMVP		0.86
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1344295491; hg19: chrX-49079540;