12-51469724-G-T

Position:

• chr12-51469724-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001039960.3(SLC4A8):​c.1460G>T​(p.Cys487Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC4A8 NM_001039960.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

SLC4A8 (HGNC:11034): (solute carrier family 4 member 8) The protein encoded by this gene is a membrane protein that functions to transport sodium and bicarbonate ions across the cell membrane. The encoded protein is important for pH regulation in neurons. The activity of this protein can be inhibited by 4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid (DIDS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC4A8. . Gene score misZ 4.0551 (greater than the threshold 3.09). Trascript score misZ 4.6916 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A8	NM_001039960.3	c.1460G>T	p.Cys487Phe	missense_variant	12/25	ENST00000453097.7	NP_001035049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A8	ENST00000453097.7	c.1460G>T	p.Cys487Phe	missense_variant	12/25	1	NM_001039960.3	ENSP00000405812	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 22, 2021

The SLC4A8 c.1460G>T (p.Cys487Phe) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggest the variant is rare. This variant lies within a helical transmembrane domain, though the function of this region has not been established. Based on the available evidence, the p.Cys487Phe variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	.;.;D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.48	.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D;.;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.67	T;.;T;T
Sift4G	Benign	0.64	T;T;T;T
Polyphen		1.0	.;.;D;.
Vest4		0.90
MutPred		0.64		.;.;Loss of catalytic residue at C487 (P = 0.1214);.;
MVP		0.54
MPC		2.1
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.55
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-51863508;