rs781923856

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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). Synonymous variant affecting the same amino acid position (i.e. A536A) has been classified as Likely benign.

• 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
• Publications: 0 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: Likely_benign. The variant received -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 VariationId is 520685.
• BS2: High AC in GnomAdExome4 at 11 XL,AD gene.

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.1606G>A	p.Ala536Thr	missense	Exon 13 of 48	NP_001243718.1	O60840-2
	CACNA1F	NM_005183.4		c.1639G>A	p.Ala547Thr	missense	Exon 13 of 48	NP_005174.2	O60840-1
	CACNA1F	NM_001256790.3		c.1444G>A	p.Ala482Thr	missense	Exon 13 of 48	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.1606G>A	p.Ala536Thr	missense	Exon 13 of 48	ENSP00000321618.6	O60840-2
	CACNA1F	ENST00000376265.2	TSL:1	c.1639G>A	p.Ala547Thr	missense	Exon 13 of 48	ENSP00000365441.2	O60840-1
	CACNA1F	ENST00000376251.5	TSL:1	c.1444G>A	p.Ala482Thr	missense	Exon 13 of 48	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000170 AC: 2 AN: 117830 AF XY: 0.0000244

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 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

African (AFR) AF: 0.00 AC: 0 AN: 25062

American (AMR) AF: 0.00 AC: 0 AN: 28185

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18665

East Asian (EAS) AF: 0.00 AC: 0 AN: 27332

South Asian (SAS) AF: 0.000120 AC: 6 AN: 49994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37791

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4088

European-Non Finnish (NFE) AF: 0.00000609 AC: 5 AN: 820541

Other (OTH) AF: 0.00 AC: 0 AN: 44462

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000194 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.81
Sift	Benign	0.10	T
Sift4G	Uncertain	0.057	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
Mutation Taster		=92/8	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs781923856; hg19: chrX-49082416;