NM_001256789.3:c.2509G>A

Variant names:

• chrX-49219668-C-T
• rs863225090
• NM_001256789.3:c.2509G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001256789.3(CACNA1F):​c.2509G>A​(p.Gly837Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000915 in 1,092,980 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.14
• Publications: 2 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-49219668-C-T is Pathogenic according to our data. Variant chrX-49219668-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217443.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	NM_001256789.3	MANE Select	c.2509G>A	p.Gly837Ser	missense	Exon 20 of 48	NP_001243718.1
	CACNA1F	NM_005183.4		c.2542G>A	p.Gly848Ser	missense	Exon 20 of 48	NP_005174.2
	CACNA1F	NM_001256790.3		c.2347G>A	p.Gly783Ser	missense	Exon 20 of 48	NP_001243719.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	ENST00000323022.10	TSL:1 MANE Select	c.2509G>A	p.Gly837Ser	missense	Exon 20 of 48	ENSP00000321618.6
	CACNA1F	ENST00000376265.2	TSL:1	c.2542G>A	p.Gly848Ser	missense	Exon 20 of 48	ENSP00000365441.2
	CACNA1F	ENST00000376251.5	TSL:1	c.2347G>A	p.Gly783Ser	missense	Exon 20 of 48	ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092980 Hom.: 0 Cov.: 33 AF XY: 0.00000278 AC XY: 1 AN XY: 359200

African (AFR) AF: 0.00 AC: 0 AN: 26289

American (AMR) AF: 0.00 AC: 0 AN: 34831

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19303

East Asian (EAS) AF: 0.00 AC: 0 AN: 29948

South Asian (SAS) AF: 0.00 AC: 0 AN: 53051

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40065

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839462

Other (OTH) AF: 0.00 AC: 0 AN: 45903

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked cone-rod dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	1.9	L
PhyloP100		6.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.81
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.90	P
Vest4		0.45
MutPred		0.47		Loss of sheet (P = 0.0315)
MVP		0.95
MPC		0.53
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.76
gMVP		0.90
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs863225090; hg19: chrX-49076127;