rs34162630

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001256789.3(CACNA1F):​c.1523G>A​(p.Arg508Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,188,489 control chromosomes in the GnomAD database, including 258 homozygotes. There are 9,016 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R508W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (28 hom., 576 hem., cov: 23)
  • Exomes 𝑓: 0.024 (230 hom. 8440 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.83
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02172777).
• BP6: Variant X-49226037-C-T is Benign according to our data. Variant chrX-49226037-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0174 (1935/110942) while in subpopulation NFE AF = 0.0262 (1385/52829). AF 95% confidence interval is 0.0251. There are 28 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1935 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.1523G>A	p.Arg508Gln	missense	Exon 13 of 48	NP_001243718.1	O60840-2
	CACNA1F	NM_005183.4		c.1556G>A	p.Arg519Gln	missense	Exon 13 of 48	NP_005174.2	O60840-1
	CACNA1F	NM_001256790.3		c.1361G>A	p.Arg454Gln	missense	Exon 13 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.1523G>A	p.Arg508Gln	missense	Exon 13 of 48	ENSP00000321618.6	O60840-2
	CACNA1F	ENST00000376265.2	TSL:1	c.1556G>A	p.Arg519Gln	missense	Exon 13 of 48	ENSP00000365441.2	O60840-1
	CACNA1F	ENST00000376251.5	TSL:1	c.1361G>A	p.Arg454Gln	missense	Exon 13 of 48	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 1939 AN: 110895 Hom.: 28 Cov.: 23

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00152

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.0212

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0108

GnomAD2 exomes AF: 0.0174 AC: 2498 AN: 143850 AF XY: 0.0183

Gnomad AFR exome AF: 0.00354

Gnomad AMR exome AF: 0.00421

Gnomad ASJ exome AF: 0.00323

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0342

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0239 AC: 25796 AN: 1077547 Hom.: 230 Cov.: 32 AF XY: 0.0240 AC XY: 8440 AN XY: 351193

African (AFR) AF: 0.00286 AC: 74 AN: 25886

American (AMR) AF: 0.00399 AC: 128 AN: 32117

Ashkenazi Jewish (ASJ) AF: 0.00242 AC: 46 AN: 19020

East Asian (EAS) AF: 0.0000689 AC: 2 AN: 29016

South Asian (SAS) AF: 0.0211 AC: 1087 AN: 51615

European-Finnish (FIN) AF: 0.0362 AC: 1416 AN: 39115

Middle Eastern (MID) AF: 0.0177 AC: 73 AN: 4115

European-Non Finnish (NFE) AF: 0.0266 AC: 22092 AN: 831342

Other (OTH) AF: 0.0194 AC: 878 AN: 45321

GnomAD4 genome AF: 0.0174 AC: 1935 AN: 110942 Hom.: 28 Cov.: 23 AF XY: 0.0173 AC XY: 576 AN XY: 33266

African (AFR) AF: 0.00262 AC: 80 AN: 30525

American (AMR) AF: 0.00713 AC: 75 AN: 10523

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 4 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3498

South Asian (SAS) AF: 0.0221 AC: 58 AN: 2626

European-Finnish (FIN) AF: 0.0321 AC: 190 AN: 5927

Middle Eastern (MID) AF: 0.0140 AC: 3 AN: 215

European-Non Finnish (NFE) AF: 0.0262 AC: 1385 AN: 52829

Other (OTH) AF: 0.0100 AC: 15 AN: 1494

Alfa AF: 0.0216 Hom.: 1398

Bravo AF: 0.0158

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0267 AC: 77

ESP6500AA AF: 0.00314 AC: 12

ESP6500EA AF: 0.0250 AC: 168

ExAC AF: 0.0158 AC: 1884

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.71
Sift	Benign	0.048	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.69
MPC		0.91
ClinPred		0.029	T
GERP RS		3.6
Varity_R		0.50
gMVP		0.81
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;