15-48207790-G-A

Position:

• chr15-48207790-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000338.3(SLC12A1):​c.71G>A​(p.Ser24Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000684 in 1,613,482 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: SLC12A1 NM_000338.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.38

Genes affected

SLC12A1 (HGNC:10910): (solute carrier family 12 member 1) This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle's loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004472792).
• BP6: Variant 15-48207790-G-A is Benign according to our data. Variant chr15-48207790-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 778549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0039 (594/152266) while in subpopulation AFR AF= 0.0137 (571/41552). AF 95% confidence interval is 0.0128. There are 4 homozygotes in gnomad4. There are 318 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.71G>A	p.Ser24Asn	missense_variant	2/27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.71G>A	p.Ser24Asn	missense_variant	2/27		NP_001171761.1
SLC12A1	NM_001384136.1	c.71G>A	p.Ser24Asn	missense_variant	2/27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.71G>A	p.Ser24Asn	missense_variant	2/27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 582 AN: 152148 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00108 AC: 270 AN: 250344 Hom.: 3 AF XY: 0.000858 AC XY: 116 AN XY: 135264

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000349 AC: 510 AN: 1461216 Hom.: 1 Cov.: 31 AF XY: 0.000285 AC XY: 207 AN XY: 726828

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152266 Hom.: 4 Cov.: 32 AF XY: 0.00427 AC XY: 318 AN XY: 74444

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000699 Hom.: 0

Bravo AF: 0.00459

ESP6500AA AF: 0.0164 AC: 72

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Benign	0.028	.;.;T;T;T;.;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.43	.;T;.;.;T;T;T;T
MetaRNN	Benign	0.0045	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-1.7	N;.;N;N;N;N;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.82	.;.;.;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	1.0	.;.;.;T;T;T;T;T
Sift4G	Benign	1.0	.;.;.;T;T;T;T;T
Polyphen		0.0	.;.;B;B;B;.;B;.
Vest4		0.070, 0.072, 0.065, 0.056, 0.048
MVP		0.78
MPC		0.13
ClinPred		0.011	T
GERP RS		5.4
Varity_R		0.037
gMVP		0.093

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: rs35342218; hg19: chr15-48499987;