rs141010716

Variant names:

• chrX-49224768-C-T
• rs141010716
• NM_001256789.3:c.1870G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001256789.3(CACNA1F):​c.1870G>A​(p.Val624Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,160,649 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V624D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., 63 hem., cov: 21)
  • Exomes 𝑓: 0.0033 (8 hom. 1046 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.448
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011872292).
• BP6: Variant X-49224768-C-T is Benign according to our data. Variant chrX-49224768-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259657.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00227 (252/110916) while in subpopulation NFE AF = 0.00405 (214/52878). AF 95% confidence interval is 0.0036. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 252 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.1870G>A	p.Val624Ile	missense	Exon 14 of 48	NP_001243718.1	O60840-2
	CACNA1F	NM_005183.4		c.1903G>A	p.Val635Ile	missense	Exon 14 of 48	NP_005174.2	O60840-1
	CACNA1F	NM_001256790.3		c.1708G>A	p.Val570Ile	missense	Exon 14 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.1870G>A	p.Val624Ile	missense	Exon 14 of 48	ENSP00000321618.6	O60840-2
	CACNA1F	ENST00000376265.2	TSL:1	c.1903G>A	p.Val635Ile	missense	Exon 14 of 48	ENSP00000365441.2	O60840-1
	CACNA1F	ENST00000376251.5	TSL:1	c.1708G>A	p.Val570Ile	missense	Exon 14 of 48	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 252 AN: 110862 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000763

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000387

Gnomad FIN AF: 0.000336

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00405

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00206 AC: 265 AN: 128537 AF XY: 0.00199

Gnomad AFR exome AF: 0.000709

Gnomad AMR exome AF: 0.000999

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000641

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00326 AC: 3421 AN: 1049733 Hom.: 8 Cov.: 28 AF XY: 0.00313 AC XY: 1046 AN XY: 334273

African (AFR) AF: 0.000679 AC: 17 AN: 25041

American (AMR) AF: 0.000817 AC: 24 AN: 29383

Ashkenazi Jewish (ASJ) AF: 0.000214 AC: 4 AN: 18659

East Asian (EAS) AF: 0.00 AC: 0 AN: 27866

South Asian (SAS) AF: 0.000179 AC: 9 AN: 50184

European-Finnish (FIN) AF: 0.00117 AC: 45 AN: 38384

Middle Eastern (MID) AF: 0.00617 AC: 25 AN: 4051

European-Non Finnish (NFE) AF: 0.00389 AC: 3155 AN: 811778

Other (OTH) AF: 0.00320 AC: 142 AN: 44387

GnomAD4 genome AF: 0.00227 AC: 252 AN: 110916 Hom.: 0 Cov.: 21 AF XY: 0.00190 AC XY: 63 AN XY: 33152

African (AFR) AF: 0.000722 AC: 22 AN: 30466

American (AMR) AF: 0.000762 AC: 8 AN: 10501

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3512

South Asian (SAS) AF: 0.000389 AC: 1 AN: 2574

European-Finnish (FIN) AF: 0.000336 AC: 2 AN: 5953

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.00405 AC: 214 AN: 52878

Other (OTH) AF: 0.00199 AC: 3 AN: 1508

Alfa AF: 0.00263 Hom.: 42

Bravo AF: 0.00202

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00329 AC: 22

ExAC AF: 0.00169 AC: 193

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	not provided (3)
-	-	1	Congenital stationary night blindness 2A (1)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Benign	0.65
DEOGEN2	Uncertain	0.48	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.45
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.39
Sift	Benign	0.55	T
Sift4G	Benign	0.38	T
Polyphen		0.66	P
Vest4		0.44
MVP		0.82
MPC		0.48
ClinPred		0.021	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.70
Mutation Taster		=100/0	polymorphism (auto)

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: rs141010716; hg19: chrX-49081230;