chr12-51469784-G-A

Variant names:

• chr12-51469784-G-A
• rs200633626
• NM_001039960.3:c.1520G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001039960.3(SLC4A8):​c.1520G>A​(p.Arg507His) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,810 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. R507C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: SLC4A8 NM_001039960.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99
• Publications: 3 publications found

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]

SLC4A8 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056529135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039960.3. 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
	SLC4A8	NM_001039960.3	MANE Select	c.1520G>A	p.Arg507His	missense	Exon 12 of 25	NP_001035049.1	Q2Y0W8-1
	SLC4A8	NM_001405270.1		c.1484G>A	p.Arg495His	missense	Exon 12 of 25	NP_001392199.1
	SLC4A8	NM_001258401.3		c.1361G>A	p.Arg454His	missense	Exon 12 of 25	NP_001245330.1	Q2Y0W8-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A8	ENST00000453097.7	TSL:1 MANE Select	c.1520G>A	p.Arg507His	missense	Exon 12 of 25	ENSP00000405812.2	Q2Y0W8-1
	SLC4A8	ENST00000358657.7	TSL:1	c.1361G>A	p.Arg454His	missense	Exon 12 of 25	ENSP00000351483.4	Q2Y0W8-5
	SLC4A8	ENST00000514353.7	TSL:1	c.1361G>A	p.Arg454His	missense	Exon 12 of 17	ENSP00000442561.2	Q2Y0W8-7

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250432 AF XY: 0.000177

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461542 Hom.: 1 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 727084

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000109 AC: 121 AN: 1111786

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74454

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.29
Sift	Benign	0.37	T
Sift4G	Benign	0.46	T
Polyphen		0.22	B
Vest4		0.13
MVP		0.068
MPC		0.85
ClinPred		0.076	T
GERP RS		4.8
Varity_R		0.096
gMVP		0.54
Mutation Taster		=70/30	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: rs200633626; hg19: chr12-51863568; COSMIC: COSV60659243; COSMIC: COSV60659243;