rs145627424

Variant names:

• chrX-49205184-C-G
• rs145627424
• NM_001256789.3:c.5854G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-49205184-C-G
• chrX-49205184-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_001256789.3(CACNA1F):​c.5854G>C​(p.Asp1952His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000579 in 1,209,539 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1952N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3117581).
• BS2: High Hemizygotes in GnomAd4 at 2 XL,AD geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.5854G>C	p.Asp1952His	missense	Exon 48 of 48	NP_001243718.1	O60840-2
	CACNA1F	NM_005183.4		c.5887G>C	p.Asp1963His	missense	Exon 48 of 48	NP_005174.2	O60840-1
	CACNA1F	NM_001256790.3		c.5692G>C	p.Asp1898His	missense	Exon 48 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.5854G>C	p.Asp1952His	missense	Exon 48 of 48	ENSP00000321618.6	O60840-2
	CACNA1F	ENST00000376265.2	TSL:1	c.5887G>C	p.Asp1963His	missense	Exon 48 of 48	ENSP00000365441.2	O60840-1
	CACNA1F	ENST00000376251.5	TSL:1	c.5692G>C	p.Asp1898His	missense	Exon 48 of 48	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112099 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182174 AF XY: 0.00

Gnomad AFR exome AF: 0.0000765

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097440 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362850

African (AFR) AF: 0.0000379 AC: 1 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54083

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40411

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841587

Other (OTH) AF: 0.0000434 AC: 2 AN: 46069

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112099 Hom.: 0 Cov.: 22 AF XY: 0.0000584 AC XY: 2 AN XY: 34253

African (AFR) AF: 0.0000972 AC: 3 AN: 30852

American (AMR) AF: 0.00 AC: 0 AN: 10604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6135

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53149

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.31	T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.2	L
PhyloP100		2.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.012	D
Sift4G	Benign	0.085	T
Polyphen		0.99	D
Vest4		0.34
MVP		0.79
MPC		0.37
ClinPred		0.20	T
GERP RS		5.0
Varity_R		0.31
gMVP		0.73
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs145627424; hg19: chrX-49061644;