NM_003040.4:c.77G>A

Variant names:

• chr7-151064227-G-A
• rs2303929
• NM_003040.4:c.77G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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 0.22 (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
• Publications: 47 publications found

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]

SLC4A2 Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 4

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• osteopetrosis, autosomal recessive 9

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003040.4. 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
	SLC4A2	NM_003040.4	MANE Select	c.77G>A	p.Gly26Glu	missense	Exon 3 of 23	NP_003031.3
	SLC4A2	NM_001199692.3		c.77G>A	p.Gly26Glu	missense	Exon 3 of 23	NP_001186621.1	P04920-1
	SLC4A2	NM_001199693.1		c.50G>A	p.Gly17Glu	missense	Exon 2 of 22	NP_001186622.1	Q59GF1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A2	ENST00000413384.7	TSL:1 MANE Select	c.77G>A	p.Gly26Glu	missense	Exon 3 of 23	ENSP00000405600.2	P04920-1
	SLC4A2	ENST00000485713.6	TSL:1	c.77G>A	p.Gly26Glu	missense	Exon 3 of 23	ENSP00000419412.1
	SLC4A2	ENST00000461735.1	TSL:1	c.35G>A	p.Gly12Glu	missense	Exon 2 of 22	ENSP00000419164.1	P04920-2

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

GnomAD2 exomes AF: 0.277 AC: 69428 AN: 250750 AF XY: 0.264

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 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

African (AFR) AF: 0.118 AC: 3948 AN: 33422

American (AMR) AF: 0.549 AC: 24527 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5671 AN: 26126

East Asian (EAS) AF: 0.295 AC: 11720 AN: 39700

South Asian (SAS) AF: 0.194 AC: 16727 AN: 86188

European-Finnish (FIN) AF: 0.271 AC: 14481 AN: 53344

Middle Eastern (MID) AF: 0.212 AC: 954 AN: 4490

European-Non Finnish (NFE) AF: 0.229 AC: 255135 AN: 1111798

Other (OTH) AF: 0.229 AC: 13823 AN: 60248

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

African (AFR) AF: 0.122 AC: 5076 AN: 41454

American (AMR) AF: 0.381 AC: 5817 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 788 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1523 AN: 5160

South Asian (SAS) AF: 0.187 AC: 898 AN: 4810

European-Finnish (FIN) AF: 0.275 AC: 2910 AN: 10574

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.233 AC: 15822 AN: 67940

Other (OTH) AF: 0.233 AC: 492 AN: 2112

Alfa AF: 0.235 Hom.: 16751

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 v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.27
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.037	D
Polyphen		0.0	B
Vest4		0.092
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2303929; hg19: chr7-150761314; COSMIC: COSV59656077; COSMIC: COSV59656077;