chrX-49205211-C-T

Position:

• chrX-49205211-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001256789.3(CACNA1F):​c.5827G>A​(p.Asp1943Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,209,136 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 51 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).

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00013 (0 hom. 46 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.01

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047239095).
• BP6: Variant X-49205211-C-T is Benign according to our data. Variant chrX-49205211-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197594.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000129 (142/1097386) while in subpopulation AMR AF= 0.00162 (57/35187). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4_exome. There are 46 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.5827G>A	p.Asp1943Asn	missense_variant	48/48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.5827G>A	p.Asp1943Asn	missense_variant	48/48	1	NM_001256789.3	ENSP00000321618
CACNA1F	ENST00000376265.2	c.5860G>A	p.Asp1954Asn	missense_variant	48/48	1		ENSP00000365441	P1
CACNA1F	ENST00000376251.5	c.5665G>A	p.Asp1889Asn	missense_variant	48/48	1		ENSP00000365427

Frequencies

GnomAD3 genomes AF: 0.0000805 AC: 9 AN: 111750 Hom.: 0 Cov.: 23 AF XY: 0.000148 AC XY: 5 AN XY: 33898

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00134

GnomAD3 exomes AF: 0.000319 AC: 58 AN: 182064 Hom.: 0 AF XY: 0.000195 AC XY: 13 AN XY: 66774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000370

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000129 AC: 142 AN: 1097386 Hom.: 0 Cov.: 30 AF XY: 0.000127 AC XY: 46 AN XY: 362788

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000927

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.0000805 AC: 9 AN: 111750 Hom.: 0 Cov.: 23 AF XY: 0.000148 AC XY: 5 AN XY: 33898

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000380

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000565

Gnomad4 OTH AF: 0.00134

Bravo AF: 0.000200

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.00

EpiControl AF: 0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;.;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.7	.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.10	T;T;T
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.90	.;.;P
Vest4		0.26
MVP		0.85
MPC		0.22
ClinPred		0.073	T
GERP RS		5.0
Varity_R		0.20
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs374663693; hg19: chrX-49061671;