chr2-161974255-C-G

Variant names:

• chr2-161974255-C-G
• rs142943771
• NM_001178015.2:c.3166C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001178015.2(SLC4A10):​c.3166C>G​(p.Gln1056Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,605,336 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: SLC4A10 NM_001178015.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 3.53
• Publications: 3 publications found

Genes affected

SLC4A10 (HGNC:13811): (solute carrier family 4 member 10) This gene belongs to a small family of sodium-coupled bicarbonate transporters (NCBTs) that regulate the intracellular pH of neurons, the secretion of bicarbonate ions across the choroid plexus, and the pH of the brain extracellular fluid. The protein encoded by this gene was initially identified as a sodium-driven chloride bicarbonate exchanger (NCBE) though there is now evidence that its sodium/bicarbonate cotransport activity is independent of any chloride ion countertransport under physiological conditions. This gene is now classified as a member A10 of the SLC4 family of transmembrane solute carriers. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, May 2010]

SLC4A10 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and characteristic brain abnormalities

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Baylor College of Medicine Research Center, G2P

ENSG00000296511 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072874725).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00152 (232/152240) while in subpopulation AFR AF = 0.00505 (210/41562). AF 95% confidence interval is 0.00449. There are 0 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001178015.2. 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
	SLC4A10	NM_001178015.2	MANE Select	c.3166C>G	p.Gln1056Glu	missense	Exon 24 of 27	NP_001171486.1
	SLC4A10	NM_001354440.2		c.3166C>G	p.Gln1056Glu	missense	Exon 24 of 26	NP_001341369.1
	SLC4A10	NM_001354460.2		c.3202C>G	p.Gln1068Glu	missense	Exon 25 of 28	NP_001341389.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A10	ENST00000446997.6	TSL:1 MANE Select	c.3166C>G	p.Gln1056Glu	missense	Exon 24 of 27	ENSP00000393066.1
	SLC4A10	ENST00000415876.6	TSL:1	c.3076C>G	p.Gln1026Glu	missense	Exon 23 of 26	ENSP00000395797.2
	SLC4A10	ENST00000272716.9	TSL:5	c.3076C>G	p.Gln1026Glu	missense	Exon 23 of 25	ENSP00000272716.5

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 232 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.000366 AC: 87 AN: 237660 AF XY: 0.000242

Gnomad AFR exome AF: 0.00427

Gnomad AMR exome AF: 0.000573

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000177 AC: 257 AN: 1453096 Hom.: 1 Cov.: 29 AF XY: 0.000159 AC XY: 115 AN XY: 721706

African (AFR) AF: 0.00483 AC: 161 AN: 33306

American (AMR) AF: 0.000482 AC: 21 AN: 43552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 83926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5754

European-Non Finnish (NFE) AF: 0.0000433 AC: 48 AN: 1107940

Other (OTH) AF: 0.000333 AC: 20 AN: 60120

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74436

African (AFR) AF: 0.00505 AC: 210 AN: 41562

American (AMR) AF: 0.000785 AC: 12 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67990

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.00168

ESP6500AA AF: 0.00536 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000414 AC: 50

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

SLC4A10-related disorder Benign:1

Apr 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.49
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.14	N
PhyloP100		3.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.91	N
REVEL	Uncertain	0.37
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.32
MVP		0.71
MPC		0.0093
ClinPred		0.021	T
GERP RS		5.2
Varity_R		0.16
gMVP		0.30
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs142943771; hg19: chr2-162830765;