chrX-49225954-C-T

Variant names:

• chrX-49225954-C-T
• rs781923856
• NM_001256789.3:c.1606G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5 BS2

The NM_001256789.3(CACNA1F):​c.1606G>A​(p.Ala536Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,056,120 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.96

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 Likely_benign. Variant got -3 ACMG points.

• PP5: Variant X-49225954-C-T is Pathogenic according to our data. Variant chrX-49225954-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520685.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.1606G>A	p.Ala536Thr	missense_variant	Exon 13 of 48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.1639G>A	p.Ala547Thr	missense_variant	Exon 13 of 48		NP_005174.2
CACNA1F	NM_001256790.3	c.1444G>A	p.Ala482Thr	missense_variant	Exon 13 of 48		NP_001243719.1
CACNA1F	XM_011543983.3	c.1444G>A	p.Ala482Thr	missense_variant	Exon 13 of 47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.1606G>A	p.Ala536Thr	missense_variant	Exon 13 of 48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.1639G>A	p.Ala547Thr	missense_variant	Exon 13 of 48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.1444G>A	p.Ala482Thr	missense_variant	Exon 13 of 48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000170 AC: 2 AN: 117830 Hom.: 0 AF XY: 0.0000244 AC XY: 1 AN XY: 40958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000698

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 11 AN: 1056120 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 4 AN XY: 345238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000609

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ExAC AF: 0.0000194 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 20, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1F protein function. ClinVar contains an entry for this variant (Variation ID: 520685). This variant has not been reported in the literature in individuals affected with CACNA1F-related conditions. This variant is present in population databases (rs781923856, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 547 of the CACNA1F protein (p.Ala547Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	.;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Pathogenic	0.81
Sift	Benign	0.10	T;T;T
Sift4G	Uncertain	0.057	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.64
MutPred		0.51		.;.;Gain of disorder (P = 0.1043);
MVP		0.97
MPC		0.64
ClinPred		0.81	D
GERP RS		3.6
Varity_R		0.34
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs781923856; hg19: chrX-49082416;