chr2-74222931-C-A

Variant names:

• chr2-74222931-C-A
• rs36081793
• NM_133478.3:c.3268G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_133478.3(SLC4A5):​c.3268G>T​(p.Val1090Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC4A5 NM_133478.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.601
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26866645).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133478.3. 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
	SLC4A5	NM_133478.3	MANE Select	c.3268G>T	p.Val1090Phe	missense	Exon 29 of 31	NP_597812.1	Q9BY07-3
	SLC4A5	NM_021196.3		c.3316G>T	p.Val1106Phe	missense	Exon 25 of 26	NP_067019.3	Q9BY07-1
	SLC4A5	NM_001386136.1		c.2920G>T	p.Val974Phe	missense	Exon 23 of 25	NP_001373065.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A5	ENST00000394019.7	TSL:5 MANE Select	c.3268G>T	p.Val1090Phe	missense	Exon 29 of 31	ENSP00000377587.2	Q9BY07-3
	SLC4A5	ENST00000377632.5	TSL:1	c.3025G>T	p.Val1009Phe	missense	Exon 22 of 23	ENSP00000366859.1	Q9BY07-4
	SLC4A5	ENST00000358683.8	TSL:1	c.2962G>T	p.Val988Phe	missense	Exon 23 of 24	ENSP00000351513.4	Q9BY07-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460252 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726362

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85938

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111246

Other (OTH) AF: 0.00 AC: 0 AN: 60318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.60
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.016	D
Sift4G	Benign	0.27	T
Polyphen		0.26	B
Vest4		0.47
MutPred		0.12		Loss of sheet (P = 0.0817)
MVP		0.51
MPC		0.45
ClinPred		0.73	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.48
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs36081793; hg19: chr2-74450058;