2-74304705-G-C

Variant names:

• chr2-74304705-G-C
• rs12991424
• NM_133478.3:c.80-25C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_133478.3(SLC4A5):​c.80-25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,586,378 control chromosomes in the GnomAD database, including 870 homozygotes. 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: 𝑓 0.024 (67 hom., cov: 32)
  • Exomes 𝑓: 0.030 (803 hom.)
• Consequence: SLC4A5 NM_133478.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.743
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3651/152282) while in subpopulation NFE AF = 0.034 (2312/68010). AF 95% confidence interval is 0.0328. There are 67 homozygotes in GnomAd4. There are 1826 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 67 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A5	NM_133478.3	MANE Select	c.80-25C>G		intron	N/A	NP_597812.1
	SLC4A5	NM_021196.3		c.80-25C>G		intron	N/A	NP_067019.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A5	ENST00000394019.7	TSL:5 MANE Select	c.80-25C>G		intron	N/A	ENSP00000377587.2
	SLC4A5	ENST00000377632.5	TSL:1	c.80-25C>G		intron	N/A	ENSP00000366859.1
	SLC4A5	ENST00000358683.8	TSL:1	c.79+10240C>G		intron	N/A	ENSP00000351513.4

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3653 AN: 152164 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00913

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0265 AC: 6219 AN: 234500 AF XY: 0.0261

Gnomad AFR exome AF: 0.00499

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0741

Gnomad NFE exome AF: 0.0338

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0304 AC: 43542 AN: 1434096 Hom.: 803 Cov.: 29 AF XY: 0.0297 AC XY: 21078 AN XY: 710634

African (AFR) AF: 0.00465 AC: 150 AN: 32250

American (AMR) AF: 0.0143 AC: 572 AN: 40108

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 383 AN: 24964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39044

South Asian (SAS) AF: 0.00846 AC: 699 AN: 82612

European-Finnish (FIN) AF: 0.0711 AC: 3770 AN: 52988

Middle Eastern (MID) AF: 0.0176 AC: 99 AN: 5632

European-Non Finnish (NFE) AF: 0.0331 AC: 36294 AN: 1097332

Other (OTH) AF: 0.0266 AC: 1575 AN: 59166

GnomAD4 genome AF: 0.0240 AC: 3651 AN: 152282 Hom.: 67 Cov.: 32 AF XY: 0.0245 AC XY: 1826 AN XY: 74466

African (AFR) AF: 0.00510 AC: 212 AN: 41558

American (AMR) AF: 0.0141 AC: 215 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00934 AC: 45 AN: 4816

European-Finnish (FIN) AF: 0.0689 AC: 732 AN: 10620

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0340 AC: 2312 AN: 68010

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.0285 Hom.: 21

Bravo AF: 0.0190

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.60
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs12991424; hg19: chr2-74531832;