X-49212679-G-T

Variant names:

• chrX-49212679-G-T
• rs144131971
• NM_001256789.3:c.3930C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001256789.3(CACNA1F):​c.3930C>A​(p.Ile1310Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,207,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 315 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 0.00064 (0 hom., 20 hem., cov: 23)
  • Exomes 𝑓: 0.00082 (0 hom. 295 hem.)
• Consequence: CACNA1F NM_001256789.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.44

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant X-49212679-G-T is Benign according to our data. Variant chrX-49212679-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166777.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=3.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000644 (72/111823) while in subpopulation NFE AF= 0.00121 (64/53101). AF 95% confidence interval is 0.000968. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.3930C>A	p.Ile1310Ile	synonymous_variant	Exon 33 of 48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.3930C>A	p.Ile1310Ile	synonymous_variant	Exon 33 of 48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.3963C>A	p.Ile1321Ile	synonymous_variant	Exon 33 of 48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.3768C>A	p.Ile1256Ile	synonymous_variant	Exon 33 of 48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 72 AN: 111769 Hom.: 0 Cov.: 23 AF XY: 0.000589 AC XY: 20 AN XY: 33929

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000949

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000492

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000557 AC: 100 AN: 179509 Hom.: 0 AF XY: 0.000576 AC XY: 37 AN XY: 64247

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.0000736

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000192

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000818 AC: 897 AN: 1096105 Hom.: 0 Cov.: 31 AF XY: 0.000816 AC XY: 295 AN XY: 361525

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000570

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000222

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000478

GnomAD4 genome AF: 0.000644 AC: 72 AN: 111823 Hom.: 0 Cov.: 23 AF XY: 0.000588 AC XY: 20 AN XY: 33993

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.0000948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000492

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000691 Hom.: 6

Bravo AF: 0.000480

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

Jan 21, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.8
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144131971; hg19: chrX-49069139;