5-128134167-A-G

Variant names:

• chr5-128134167-A-G
• rs2228112
• NM_001046.3:c.1191A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001046.3(SLC12A2):​c.1191A>G​(p.Glu397Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,498,932 control chromosomes in the GnomAD database, including 52,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11677 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40519 hom.)
• Consequence: SLC12A2 NM_001046.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0110
• Publications: 19 publications found

Genes affected

SLC12A2 (HGNC:10911): (solute carrier family 12 member 2) The protein encoded by this gene mediates sodium and chloride transport and reabsorption. The encoded protein is a membrane protein and is important in maintaining proper ionic balance and cell volume. This protein is phosphorylated in response to DNA damage. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

SLC12A2 Gene-Disease associations (from GenCC):

• Delpire-McNeill syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal dominant 78

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Kilquist syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-128134167-A-G is Benign according to our data. Variant chr5-128134167-A-G is described in ClinVar as Benign. ClinVar VariationId is 1262133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.011 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001046.3. 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
	SLC12A2	NM_001046.3	MANE Select	c.1191A>G	p.Glu397Glu	splice_region synonymous	Exon 6 of 27	NP_001037.1
	SLC12A2	NM_001256461.2		c.1191A>G	p.Glu397Glu	splice_region synonymous	Exon 6 of 26	NP_001243390.1
	SLC12A2	NR_046207.2		n.1380A>G		splice_region non_coding_transcript_exon	Exon 6 of 27

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A2	ENST00000262461.7	TSL:1 MANE Select	c.1191A>G	p.Glu397Glu	splice_region synonymous	Exon 6 of 27	ENSP00000262461.2
	SLC12A2	ENST00000343225.4	TSL:1	c.1191A>G	p.Glu397Glu	splice_region synonymous	Exon 6 of 26	ENSP00000340878.4
	SLC12A2	ENST00000509205.5	TSL:1	n.1191A>G		splice_region non_coding_transcript_exon	Exon 6 of 27	ENSP00000427109.1

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52400 AN: 151734 Hom.: 11641 Cov.: 32

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.278 AC: 69070 AN: 248184 AF XY: 0.262

Gnomad AFR exome AF: 0.642

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.331

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.231 AC: 311594 AN: 1347080 Hom.: 40519 Cov.: 20 AF XY: 0.229 AC XY: 154554 AN XY: 676250

African (AFR) AF: 0.639 AC: 19540 AN: 30580

American (AMR) AF: 0.400 AC: 17631 AN: 44044

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 6768 AN: 25116

East Asian (EAS) AF: 0.352 AC: 13667 AN: 38820

South Asian (SAS) AF: 0.213 AC: 17558 AN: 82434

European-Finnish (FIN) AF: 0.217 AC: 11541 AN: 53152

Middle Eastern (MID) AF: 0.203 AC: 1067 AN: 5244

European-Non Finnish (NFE) AF: 0.208 AC: 210146 AN: 1011324

Other (OTH) AF: 0.243 AC: 13676 AN: 56366

GnomAD4 genome AF: 0.346 AC: 52492 AN: 151852 Hom.: 11677 Cov.: 32 AF XY: 0.345 AC XY: 25586 AN XY: 74206

African (AFR) AF: 0.631 AC: 26167 AN: 41452

American (AMR) AF: 0.347 AC: 5292 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 899 AN: 3464

East Asian (EAS) AF: 0.334 AC: 1728 AN: 5168

South Asian (SAS) AF: 0.220 AC: 1059 AN: 4804

European-Finnish (FIN) AF: 0.210 AC: 2222 AN: 10570

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.209 AC: 14203 AN: 67818

Other (OTH) AF: 0.306 AC: 647 AN: 2112

Alfa AF: 0.255 Hom.: 6042

Bravo AF: 0.371

Asia WGS AF: 0.339 AC: 1177 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.0
DANN	Benign	0.76
PhyloP100		0.011
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2228112; hg19: chr5-127469859; COSMIC: COSV52469061;