rs2303929

Positions:

• chr7-151064227-G-A
• chr7-151064227-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003040.4(SLC4A2):​c.77G>A​(p.Gly26Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,612,016 control chromosomes in the GnomAD database, including 48,916 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (4284 hom., cov: 30)
  • Exomes 𝑓: 0.24 (44632 hom.)
• Consequence: SLC4A2 NM_003040.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.271

Genes affected

SLC4A2 (HGNC:11028): (solute carrier family 4 member 2) This gene encodes a member of the anion exchanger family of membrane transport proteins. The encoded protein regulates intracellular pH, biliary bicarbonate secretion, and chloride uptake. Reduced expression of this gene may be associated with primary biliary cirrhosis (PBC) in human patients, while differential expression of this gene may be associated with malignant hepatocellular carcinoma, colon and gastric cancers. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4443865E-4).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A2	NM_003040.4	c.77G>A	p.Gly26Glu	missense_variant	3/23	ENST00000413384.7	NP_003031.3
SLC4A2	NM_001199692.3	c.77G>A	p.Gly26Glu	missense_variant	3/23		NP_001186621.1
SLC4A2	NM_001199693.1	c.50G>A	p.Gly17Glu	missense_variant	2/22		NP_001186622.1
SLC4A2	NM_001199694.2	c.35G>A	p.Gly12Glu	missense_variant	2/22		NP_001186623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A2	ENST00000413384.7	c.77G>A	p.Gly26Glu	missense_variant	3/23	1	NM_003040.4	ENSP00000405600	P1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33717 AN: 151878 Hom.: 4272 Cov.: 30

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.237

GnomAD3 exomes AF: 0.277 AC: 69428 AN: 250750 Hom.: 11818 AF XY: 0.264 AC XY: 35894 AN XY: 135732

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.565

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.286

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.238 AC: 346986 AN: 1460020 Hom.: 44632 Cov.: 38 AF XY: 0.236 AC XY: 171050 AN XY: 726324

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.549

Gnomad4 ASJ exome AF: 0.217

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.271

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.222 AC: 33733 AN: 151996 Hom.: 4284 Cov.: 30 AF XY: 0.227 AC XY: 16851 AN XY: 74286

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.381

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.233

Alfa AF: 0.234 Hom.: 7412

Bravo AF: 0.234

TwinsUK AF: 0.221 AC: 819

ALSPAC AF: 0.241 AC: 929

ESP6500AA AF: 0.133 AC: 588

ESP6500EA AF: 0.226 AC: 1943

ExAC AF: 0.263 AC: 31883

Asia WGS AF: 0.240 AC: 835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.0065	T;T;T;T;.;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.75	T;.;T;T;T;T;T;T;T
MetaRNN	Benign	0.00024	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.20	N;N;N;N;N;N;D;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.037	D;T;T;T;T;D;D;T;T
Polyphen		0.0	.;B;B;.;.;.;.;.;B
Vest4		0.092, 0.037, 0.075, 0.077
MPC		0.79
ClinPred		0.0032	T
GERP RS		-0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2303929; hg19: chr7-150761314; COSMIC: COSV59656077; COSMIC: COSV59656077;