rs781923569

Variant names:

• chrX-49231744-C-T
• rs781923569
• NM_001256789.3:c.209G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001256789.3(CACNA1F):​c.209G>A​(p.Arg70Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,097,683 control chromosomes in the GnomAD database, including 1 homozygotes. There are 10 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000030 (1 hom. 10 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.80
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant X-49231744-C-T is Benign according to our data. Variant chrX-49231744-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191248.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000301 (33/1097683) while in subpopulation MID AF = 0.00339 (14/4126). AF 95% confidence interval is 0.00205. There are 1 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 33 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.209G>A	p.Arg70Gln	missense	Exon 2 of 48	NP_001243718.1	O60840-2
	CACNA1F	NM_005183.4		c.209G>A	p.Arg70Gln	missense	Exon 2 of 48	NP_005174.2	O60840-1
	CACNA1F	NM_001256790.3		c.66-52G>A		intron	N/A	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.209G>A	p.Arg70Gln	missense	Exon 2 of 48	ENSP00000321618.6	O60840-2
	CACNA1F	ENST00000376265.2	TSL:1	c.209G>A	p.Arg70Gln	missense	Exon 2 of 48	ENSP00000365441.2	O60840-1
	CACNA1F	ENST00000376251.5	TSL:1	c.66-52G>A		intron	N/A	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000274 AC: 5 AN: 182563 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000491

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 33 AN: 1097683 Hom.: 1 Cov.: 31 AF XY: 0.0000275 AC XY: 10 AN XY: 363065

African (AFR) AF: 0.0000379 AC: 1 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30203

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40411

Middle Eastern (MID) AF: 0.00339 AC: 14 AN: 4126

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 841782

Other (OTH) AF: 0.0000434 AC: 2 AN: 46053

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.46		Loss of MoRF binding (P = 0.0322)
MVP		0.84
MPC		0.89
ClinPred		0.64	D
GERP RS		5.2
Varity_R		0.54
gMVP		0.75
Mutation Taster		=76/24	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: rs781923569; hg19: chrX-49088206; COSMIC: COSV100545354; COSMIC: COSV100545354;