X-49219318-C-T

Variant names:

• chrX-49219318-C-T
• rs41312124
• NM_001256789.3:c.2673+3G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256789.3(CACNA1F):​c.2673+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,205,572 control chromosomes in the GnomAD database, including 1,438 homozygotes. There are 21,173 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (84 hom., 1330 hem., cov: 22)
  • Exomes 𝑓: 0.057 (1354 hom. 19843 hem.)
• Consequence: CACNA1F NM_001256789.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002534
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.999
• Publications: 4 publications found

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]

CACNA1F Gene-Disease associations (from GenCC):

• Aland island eye disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• CACNA1F-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness 2A

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• X-linked cone-rod dystrophy 3

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant X-49219318-C-T is Benign according to our data. Variant chrX-49219318-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256789.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	NM_001256789.3	MANE Select	c.2673+3G>A		splice_region intron	N/A	NP_001243718.1	O60840-2
	CACNA1F	NM_005183.4		c.2706+3G>A		splice_region intron	N/A	NP_005174.2	O60840-1
	CACNA1F	NM_001256790.3		c.2511+3G>A		splice_region intron	N/A	NP_001243719.1	O60840-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	ENST00000323022.10	TSL:1 MANE Select	c.2673+3G>A		splice_region intron	N/A	ENSP00000321618.6	O60840-2
	CACNA1F	ENST00000376265.2	TSL:1	c.2706+3G>A		splice_region intron	N/A	ENSP00000365441.2	O60840-1
	CACNA1F	ENST00000376251.5	TSL:1	c.2511+3G>A		splice_region intron	N/A	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 4516 AN: 111126 Hom.: 84 Cov.: 22

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.0849

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0638

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0212

Gnomad FIN AF: 0.0809

Gnomad MID AF: 0.0378

Gnomad NFE AF: 0.0595

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0431 AC: 7500 AN: 174086 AF XY: 0.0416

Gnomad AFR exome AF: 0.00741

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.0623

Gnomad EAS exome AF: 0.0000740

Gnomad FIN exome AF: 0.0857

Gnomad NFE exome AF: 0.0618

Gnomad OTH exome AF: 0.0429

GnomAD4 exome AF: 0.0567 AC: 62073 AN: 1094392 Hom.: 1354 Cov.: 33 AF XY: 0.0550 AC XY: 19843 AN XY: 360494

African (AFR) AF: 0.00660 AC: 174 AN: 26355

American (AMR) AF: 0.0159 AC: 557 AN: 34994

Ashkenazi Jewish (ASJ) AF: 0.0638 AC: 1234 AN: 19330

East Asian (EAS) AF: 0.0000995 AC: 3 AN: 30150

South Asian (SAS) AF: 0.0215 AC: 1151 AN: 53456

European-Finnish (FIN) AF: 0.0849 AC: 3418 AN: 40248

Middle Eastern (MID) AF: 0.0308 AC: 108 AN: 3510

European-Non Finnish (NFE) AF: 0.0632 AC: 53092 AN: 840441

Other (OTH) AF: 0.0509 AC: 2336 AN: 45908

GnomAD4 genome AF: 0.0406 AC: 4518 AN: 111180 Hom.: 84 Cov.: 22 AF XY: 0.0398 AC XY: 1330 AN XY: 33376

African (AFR) AF: 0.00908 AC: 278 AN: 30605

American (AMR) AF: 0.0240 AC: 251 AN: 10476

Ashkenazi Jewish (ASJ) AF: 0.0638 AC: 169 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3516

South Asian (SAS) AF: 0.0216 AC: 57 AN: 2634

European-Finnish (FIN) AF: 0.0809 AC: 485 AN: 5995

Middle Eastern (MID) AF: 0.0461 AC: 10 AN: 217

European-Non Finnish (NFE) AF: 0.0595 AC: 3147 AN: 52910

Other (OTH) AF: 0.0424 AC: 64 AN: 1508

Alfa AF: 0.0530 Hom.: 882

Bravo AF: 0.0358

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Aland island eye disease (1)
-	-	1	Congenital stationary night blindness 2A (1)
-	-	1	X-linked cone-rod dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.60
PhyloP100		1.0
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs41312124; hg19: chrX-49075777;