rs368228324

Variant names:

• chr7-151064872-G-A
• rs368228324
• NM_003040.4:c.484G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003040.4(SLC4A2):​c.484G>A​(p.Ala162Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SLC4A2 NM_003040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.10

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0099212825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A2	NM_003040.4	c.484G>A	p.Ala162Thr	missense_variant	Exon 5 of 23	ENST00000413384.7	NP_003031.3
SLC4A2	NM_001199692.3	c.484G>A	p.Ala162Thr	missense_variant	Exon 5 of 23		NP_001186621.1
SLC4A2	NM_001199693.1	c.457G>A	p.Ala153Thr	missense_variant	Exon 4 of 22		NP_001186622.1
SLC4A2	NM_001199694.2	c.442G>A	p.Ala148Thr	missense_variant	Exon 4 of 22		NP_001186623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A2	ENST00000413384.7	c.484G>A	p.Ala162Thr	missense_variant	Exon 5 of 23	1	NM_003040.4	ENSP00000405600.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251246 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1461700 Hom.: 0 Cov.: 34 AF XY: 0.000157 AC XY: 114 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000997

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000710

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.484G>A (p.A162T) alteration is located in exon 5 (coding exon 4) of the SLC4A2 gene. This alteration results from a G to A substitution at nucleotide position 484, causing the alanine (A) at amino acid position 162 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.049
DANN	Benign	0.65
DEOGEN2	Benign	0.052	T;T;T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.68	.;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0099	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.71	N;N;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.24	N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.33	T;T;T;T;T
Sift4G	Benign	0.82	T;T;T;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.060
MVP		0.37
MPC		0.48
ClinPred		0.029	T
GERP RS		-9.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.21

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: rs368228324; hg19: chr7-150761959;