X-49215262-G-A

Position:

• chrX-49215262-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001256789.3(CACNA1F):​c.3439-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,207,806 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,084 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 51 hem., cov: 22)
  • Exomes 𝑓: 0.0027 (5 hom. 1033 hem.)
• Consequence: CACNA1F NM_001256789.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.20

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 (BayesDel_noAF=-0.84).
• BP6: Variant X-49215262-G-A is Benign according to our data. Variant chrX-49215262-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49215262-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00189 (209/110691) while in subpopulation SAS AF= 0.0043 (11/2560). AF 95% confidence interval is 0.00241. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 51 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.3439-18C>T		intron_variant		ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.3439-18C>T		intron_variant		1	NM_001256789.3	ENSP00000321618
CACNA1F	ENST00000376251.5	c.3277-18C>T		intron_variant		1		ENSP00000365427
CACNA1F	ENST00000376265.2	c.3472-18C>T		intron_variant		1		ENSP00000365441	P1

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 210 AN: 110640 Hom.: 0 Cov.: 22 AF XY: 0.00155 AC XY: 51 AN XY: 32836

Gnomad AFR AF: 0.000792

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00172

Gnomad ASJ AF: 0.00686

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00428

Gnomad FIN AF: 0.000505

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00405

GnomAD3 exomes AF: 0.00278 AC: 504 AN: 181566 Hom.: 5 AF XY: 0.00314 AC XY: 208 AN XY: 66140

Gnomad AFR exome AF: 0.000537

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00590

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00770

Gnomad FIN exome AF: 0.000382

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.00400

GnomAD4 exome AF: 0.00268 AC: 2937 AN: 1097115 Hom.: 5 Cov.: 32 AF XY: 0.00285 AC XY: 1033 AN XY: 362507

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00267

Gnomad4 ASJ exome AF: 0.00511

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00702

Gnomad4 FIN exome AF: 0.000247

Gnomad4 NFE exome AF: 0.00254

Gnomad4 OTH exome AF: 0.00345

GnomAD4 genome AF: 0.00189 AC: 209 AN: 110691 Hom.: 0 Cov.: 22 AF XY: 0.00155 AC XY: 51 AN XY: 32897

Gnomad4 AFR AF: 0.000790

Gnomad4 AMR AF: 0.00172

Gnomad4 ASJ AF: 0.00686

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00430

Gnomad4 FIN AF: 0.000505

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00400

Alfa AF: 0.00232 Hom.: 20

Bravo AF: 0.00197

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Ocular albinism, type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Congenital stationary night blindness 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

X-linked cone-rod dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.62

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: rs199764042; hg19: chrX-49071722;