X-49231912-G-A

Position:

• chrX-49231912-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256789.3(CACNA1F):​c.41C>T​(p.Pro14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,175,821 control chromosomes in the GnomAD database, including 699 homozygotes. There are 3,183 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.049 (350 hom., 1441 hem., cov: 23)
  • Exomes 𝑓: 0.0058 (349 hom. 1742 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.50

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013768077).
• BP6: Variant X-49231912-G-A is Benign according to our data. Variant chrX-49231912-G-A is described in ClinVar as [Benign]. Clinvar id is 166780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49231912-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1F	NM_001256789.3	c.41C>T	p.Pro14Leu	missense_variant	2/48	ENST00000323022.10
CACNA1F	NM_005183.4	c.41C>T	p.Pro14Leu	missense_variant	2/48
CACNA1F	NM_001256790.3	c.66-220C>T		intron_variant
CACNA1F	XM_011543983.3	c.66-220C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1F	ENST00000323022.10	c.41C>T	p.Pro14Leu	missense_variant	2/48	1	NM_001256789.3
CACNA1F	ENST00000376265.2	c.41C>T	p.Pro14Leu	missense_variant	2/48	1		P1
CACNA1F	ENST00000376251.5	c.66-220C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 5443 AN: 112170 Hom.: 350 Cov.: 23 AF XY: 0.0414 AC XY: 1421 AN XY: 34342

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.00150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000582

Gnomad OTH AF: 0.0323

GnomAD3 exomes AF: 0.0149 AC: 1869 AN: 125838 Hom.: 125 AF XY: 0.0100 AC XY: 401 AN XY: 39910

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.00826

Gnomad ASJ exome AF: 0.000778

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00839

GnomAD4 exome AF: 0.00585 AC: 6220 AN: 1063599 Hom.: 349 Cov.: 31 AF XY: 0.00504 AC XY: 1742 AN XY: 345867

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.00984

Gnomad4 ASJ exome AF: 0.000640

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.0000816

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0487 AC: 5466 AN: 112222 Hom.: 350 Cov.: 23 AF XY: 0.0419 AC XY: 1441 AN XY: 34404

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.00150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000582

Gnomad4 OTH AF: 0.0319

Alfa AF: 0.00984 Hom.: 354

Bravo AF: 0.0567

ESP6500AA AF: 0.162 AC: 614

ESP6500EA AF: 0.000449 AC: 3

ExAC AF: 0.0147 AC: 1659

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	.;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.020	P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.23	T;T
Polyphen		0.0020	.;B
Vest4		0.056
MPC		0.34
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.19
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6520408; hg19: chrX-49088374;