2-74262196-C-T

Position:

• chr2-74262196-C-T

Variant summary

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

The NM_133478.3(SLC4A5):​c.752G>A​(p.Ser251Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,541,390 control chromosomes in the GnomAD database, including 1,690 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.087 (560 hom., cov: 28)
  • Exomes 𝑓: 0.030 (1130 hom.)
• Consequence: SLC4A5 NM_133478.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.775

Genes affected

SLC4A5 (HGNC:18168): (solute carrier family 4 member 5) This gene encodes a member of the sodium bicarbonate cotransporter (NBC) family, part of the bicarbonate transporter superfamily. Sodium bicarbonate cotransporters are involved in intracellular pH regulation and electroneural or electrogenic sodium bicarbonate transport. This protein is thought to be an integral membrane protein. Multiple transcript variants encoding different isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000264324 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013481379).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A5	NM_133478.3	c.752G>A	p.Ser251Asn	missense_variant	11/31	ENST00000394019.7	NP_597812.1
SLC4A5	NM_021196.3	c.752G>A	p.Ser251Asn	missense_variant	6/26		NP_067019.3
SLC4A5	NM_001386136.1	c.404G>A	p.Ser135Asn	missense_variant	5/25		NP_001373065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A5	ENST00000394019.7	c.752G>A	p.Ser251Asn	missense_variant	11/31	5	NM_133478.3	ENSP00000377587.2
ENSG00000264324	ENST00000451608.2	n.*1340G>A		non_coding_transcript_exon_variant	16/39	5		ENSP00000416453.2
ENSG00000264324	ENST00000451608.2	n.*1340G>A		3_prime_UTR_variant	16/39	5		ENSP00000416453.2

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 9339 AN: 107826 Hom.: 558 Cov.: 28

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0756

Gnomad FIN AF: 0.0264

Gnomad MID AF: 0.116

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0800

GnomAD3 exomes AF: 0.0367 AC: 9102 AN: 247882 Hom.: 352 AF XY: 0.0369 AC XY: 4947 AN XY: 134118

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0682

Gnomad EAS exome AF: 0.00450

Gnomad SAS exome AF: 0.0603

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0298 AC: 42771 AN: 1433446 Hom.: 1130 Cov.: 31 AF XY: 0.0306 AC XY: 21839 AN XY: 712610

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0710

Gnomad4 EAS exome AF: 0.00641

Gnomad4 SAS exome AF: 0.0641

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.0234

Gnomad4 OTH exome AF: 0.0355

GnomAD4 genome AF: 0.0866 AC: 9349 AN: 107944 Hom.: 560 Cov.: 28 AF XY: 0.0849 AC XY: 4561 AN XY: 53706

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.0374

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.0746

Gnomad4 FIN AF: 0.0264

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0795

Alfa AF: 0.0325 Hom.: 351

Bravo AF: 0.0661

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.148 AC: 653

ESP6500EA AF: 0.0253 AC: 218

ExAC AF: 0.0394 AC: 4781

Asia WGS AF: 0.0370 AC: 127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.9
DANN	Benign	0.85
DEOGEN2	Benign	0.090	.;.;T;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.54	.;T;T;T;T;.
MetaRNN	Benign	0.0013	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;N;N;.;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.079
Sift	Benign	0.29	T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.044
MPC		0.24
ClinPred		0.00017	T
GERP RS		1.3
Varity_R		0.085
gMVP		0.28

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: rs17009792; hg19: chr2-74489323; COSMIC: COSV61026673; COSMIC: COSV61026673;