7-151064878-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003040.4(SLC4A2):c.490C>T(p.Arg164Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R164Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SLC4A2 NM_003040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.261

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC4A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.1291708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A2	NM_003040.4	c.490C>T	p.Arg164Trp	missense_variant	5/23	ENST00000413384.7
SLC4A2	NM_001199692.3	c.490C>T	p.Arg164Trp	missense_variant	5/23
SLC4A2	NM_001199693.1	c.463C>T	p.Arg155Trp	missense_variant	4/22
SLC4A2	NM_001199694.2	c.448C>T	p.Arg150Trp	missense_variant	4/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A2	ENST00000413384.7	c.490C>T	p.Arg164Trp	missense_variant	5/23	1	NM_003040.4	P1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000441

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251264 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135852

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000287 AC: 420 AN: 1461702 Hom.: 0 Cov.: 34 AF XY: 0.000289 AC XY: 210 AN XY: 727178

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74326

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.490C>T (p.R164W) alteration is located in exon 5 (coding exon 4) of the SLC4A2 gene. This alteration results from a C to T substitution at nucleotide position 490, causing the arginine (R) at amino acid position 164 to be replaced by a tryptophan (W). 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	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.093
FATHMM_MKL	Benign	0.46	N
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;N;D;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.015	D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.45
MVP		0.76
MPC		1.4
ClinPred		0.17	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs138877524; hg19: chr7-150761965;