9-19516337-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_020344.4(SLC24A2):c.1802A>G(p.Asn601Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000819 in 1,614,096 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (19 hom.)
• Consequence: SLC24A2 NM_020344.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.97

Genes affected

SLC24A2 (HGNC:10976): (solute carrier family 24 member 2) This gene encodes a member of the calcium/cation antiporter superfamily of transport proteins. The encoded protein belongs to the SLC24 branch of exchangers, which can mediate the extrusion of one Ca2+ ion and one K+ ion in exchange for four Na+ ions. This family member is a retinal cone/brain exchanger that can mediate a light-induced decrease in free Ca2+ concentration. This protein may also play a neuroprotective role during ischemic brain injury. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

LOC105375988 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010553718).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00215 (328/152282) while in subpopulation AMR AF= 0.0203 (310/15302). AF 95% confidence interval is 0.0184. There are 2 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A2	NM_020344.4	c.1802A>G	p.Asn601Ser	missense_variant	11/11	ENST00000341998.7
LOC105375988	XR_007061431.1	n.692+28775T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A2	ENST00000341998.7	c.1802A>G	p.Asn601Ser	missense_variant	11/11	1	NM_020344.4	P3
SLC24A2	ENST00000286344.4	c.1751A>G	p.Asn584Ser	missense_variant	10/10	1		A1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0203

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: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00282 AC: 707 AN: 250796 Hom.: 14 AF XY: 0.00223 AC XY: 302 AN XY: 135518

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000680 AC: 994 AN: 1461814 Hom.: 19 Cov.: 32 AF XY: 0.000598 AC XY: 435 AN XY: 727200

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74456

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.00311

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00194 AC: 235

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 20, 2017

- -

Abnormal retinal morphology Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The p.Asn601Ser variant has been identified in an individual with retinal disease affecting cone photoreceptors (PMID: 12037007), and has been identified in >1% of Latino chromosomes and 5 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the Asn601Ser variant may not impact protein function (PMID: 12037007). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for retinal disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.48
Sift	Benign	0.11	T;T
Sift4G	Benign	0.062	T;T
Polyphen		0.93	P;P
Vest4		0.66
MVP		0.92
MPC		0.43
ClinPred		0.037	T
GERP RS		5.2
Varity_R		0.28
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs61745273; hg19: chr9-19516335;