15-65625017-T-G

Variant names:

• chr15-65625017-T-G
• rs35571449
• NM_004727.3:c.937T>G

Variant summary

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

The NM_004727.3(SLC24A1):​c.937T>G​(p.Leu313Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0583 in 1,613,076 control chromosomes in the GnomAD database, including 3,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L313L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.063 (319 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2743 hom.)
• Consequence: SLC24A1 NM_004727.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.196
• Publications: 17 publications found

Genes affected

SLC24A1 (HGNC:10975): (solute carrier family 24 member 1) This gene encodes a member of the potassium-dependent sodium/calcium exchanger protein family. The encoded protein plays an important role in sodium/calcium exchange in retinal rod and cone photoreceptors by mediating the extrusion of one calcium ion and one potassium ion in exchange for four sodium ions. Mutations in this gene may play a role in congenital stationary night blindness. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

SLC24A1 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness 1D

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.0019312203).
• BP6: Variant 15-65625017-T-G is Benign according to our data. Variant chr15-65625017-T-G is described in ClinVar as Benign. ClinVar VariationId is 259527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004727.3. 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
	SLC24A1	NM_004727.3	MANE Select	c.937T>G	p.Leu313Val	missense	Exon 2 of 10	NP_004718.1	O60721-1
	SLC24A1	NM_001301032.1		c.937T>G	p.Leu313Val	missense	Exon 1 of 8	NP_001287961.1	O60721-2
	SLC24A1	NM_001301031.1		c.937T>G	p.Leu313Val	missense	Exon 1 of 8	NP_001287960.1	B4E1W0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC24A1	ENST00000261892.11	TSL:1 MANE Select	c.937T>G	p.Leu313Val	missense	Exon 2 of 10	ENSP00000261892.6	O60721-1
	SLC24A1	ENST00000546330.1	TSL:1	c.937T>G	p.Leu313Val	missense	Exon 1 of 8	ENSP00000439190.1	O60721-2
	SLC24A1	ENST00000399033.8	TSL:1	c.937T>G	p.Leu313Val	missense	Exon 1 of 8	ENSP00000381991.4	O60721-3

Frequencies

GnomAD3 genomes AF: 0.0626 AC: 9526 AN: 152094 Hom.: 320 Cov.: 32

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0642

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0707

GnomAD2 exomes AF: 0.0518 AC: 12832 AN: 247760 AF XY: 0.0530

Gnomad AFR exome AF: 0.0911

Gnomad AMR exome AF: 0.0278

Gnomad ASJ exome AF: 0.0704

Gnomad EAS exome AF: 0.0447

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0544

Gnomad OTH exome AF: 0.0592

GnomAD4 exome AF: 0.0579 AC: 84585 AN: 1460864 Hom.: 2743 Cov.: 35 AF XY: 0.0579 AC XY: 42059 AN XY: 726678

African (AFR) AF: 0.0940 AC: 3142 AN: 33430

American (AMR) AF: 0.0292 AC: 1303 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.0669 AC: 1742 AN: 26038

East Asian (EAS) AF: 0.0441 AC: 1752 AN: 39694

South Asian (SAS) AF: 0.0592 AC: 5108 AN: 86236

European-Finnish (FIN) AF: 0.0313 AC: 1668 AN: 53280

Middle Eastern (MID) AF: 0.0704 AC: 406 AN: 5766

European-Non Finnish (NFE) AF: 0.0592 AC: 65772 AN: 1111456

Other (OTH) AF: 0.0612 AC: 3692 AN: 60336

GnomAD4 genome AF: 0.0625 AC: 9520 AN: 152212 Hom.: 319 Cov.: 32 AF XY: 0.0612 AC XY: 4553 AN XY: 74422

African (AFR) AF: 0.0909 AC: 3773 AN: 41512

American (AMR) AF: 0.0411 AC: 630 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0642 AC: 223 AN: 3472

East Asian (EAS) AF: 0.0422 AC: 219 AN: 5188

South Asian (SAS) AF: 0.0555 AC: 268 AN: 4830

European-Finnish (FIN) AF: 0.0343 AC: 364 AN: 10614

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0562 AC: 3821 AN: 67966

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0579 Hom.: 855

Bravo AF: 0.0638

TwinsUK AF: 0.0623 AC: 231

ALSPAC AF: 0.0620 AC: 239

ESP6500AA AF: 0.0880 AC: 346

ESP6500EA AF: 0.0565 AC: 468

ExAC AF: 0.0519 AC: 6272

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.0604

EpiControl AF: 0.0600

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital stationary night blindness 1D (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.3
DANN	Benign	0.31
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00020	N
LIST_S2	Benign	0.065	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.20
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.033
Sift	Benign	0.15	T
Sift4G	Benign	0.48	T
Polyphen		0.0060	B
Vest4		0.014
MPC		0.22
ClinPred		0.0049	T
GERP RS		1.3
Varity_R		0.035
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

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: rs35571449; hg19: chr15-65917355; COSMIC: COSV56054508; COSMIC: COSV56054508;