chr15-48288516-T-C

Variant names:

• chr15-48288516-T-C
• rs1552311
• NM_000338.3:c.2873T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_000338.3(SLC12A1):​c.2873T>C​(p.Val958Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,432,578 control chromosomes in the GnomAD database, including 715,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V958delinsA) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 1.0 (75778 hom., cov: 31)
  • Exomes 𝑓: 1.0 (639798 hom.)
• Consequence: SLC12A1 NM_000338.3 missense, splice_region
• Scores: Splicing: ADA: 0.00002561
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.777
• Publications: 27 publications found

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]

SLC12A1 Gene-Disease associations (from GenCC):

• antenatal Bartter syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Bartter disease type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000309916 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48288516-TG-CGTT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3577326.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=5.747869E-7).
• BP6: Variant 15-48288516-T-C is Benign according to our data. Variant chr15-48288516-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000338.3. 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
	SLC12A1	NM_000338.3	MANE Select	c.2873T>C	p.Val958Ala	missense splice_region	Exon 23 of 27	NP_000329.2	Q13621-1
	SLC12A1	NM_001184832.2		c.2873T>C	p.Val958Ala	missense splice_region	Exon 23 of 27	NP_001171761.1	Q13621-3
	SLC12A1	NM_001384136.1		c.2873T>C	p.Val958Ala	missense splice_region	Exon 23 of 27	NP_001371065.1	A0A8I5KSK6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	ENST00000380993.8	TSL:5 MANE Select	c.2873T>C	p.Val958Ala	missense splice_region	Exon 23 of 27	ENSP00000370381.3	Q13621-1
	SLC12A1	ENST00000558252.5	TSL:1	n.6996T>C		splice_region non_coding_transcript_exon	Exon 19 of 23
	SLC12A1	ENST00000560692.5	TSL:1	n.7012T>C		splice_region non_coding_transcript_exon	Exon 18 of 22

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151817 AN: 152196 Hom.: 75720 Cov.: 31

Gnomad AFR AF: 0.991

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.996

GnomAD2 exomes AF: 0.999 AC: 160933 AN: 161024 AF XY: 1.00

Gnomad AFR exome AF: 0.992

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 1.00 AC: 1279929 AN: 1280264 Hom.: 639798 Cov.: 19 AF XY: 1.00 AC XY: 637983 AN XY: 638128

African (AFR) AF: 0.991 AC: 28794 AN: 29062

American (AMR) AF: 0.999 AC: 35222 AN: 35240

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 24374 AN: 24374

East Asian (EAS) AF: 1.00 AC: 35432 AN: 35432

South Asian (SAS) AF: 1.00 AC: 76117 AN: 76118

European-Finnish (FIN) AF: 1.00 AC: 49400 AN: 49400

Middle Eastern (MID) AF: 1.00 AC: 5450 AN: 5450

European-Non Finnish (NFE) AF: 1.00 AC: 971067 AN: 971080

Other (OTH) AF: 0.999 AC: 54073 AN: 54108

GnomAD4 genome AF: 0.998 AC: 151934 AN: 152314 Hom.: 75778 Cov.: 31 AF XY: 0.998 AC XY: 74287 AN XY: 74472

African (AFR) AF: 0.991 AC: 41218 AN: 41574

American (AMR) AF: 0.999 AC: 15281 AN: 15296

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5182

South Asian (SAS) AF: 1.00 AC: 4820 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68033 AN: 68034

Other (OTH) AF: 0.996 AC: 2106 AN: 2114

Alfa AF: 0.999 Hom.: 175364

Bravo AF: 0.997

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.992 AC: 4335

ESP6500EA AF: 1.00 AC: 8510

ExAC AF: 0.998 AC: 92168

Asia WGS AF: 0.999 AC: 3474 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Bartter disease type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.22
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.0	N
PhyloP100		0.78
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.17
ClinPred		0.0083	T
GERP RS		4.5
Varity_R		0.023
gMVP		0.21
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.050
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: rs1552311; hg19: chr15-48580713; COSMIC: COSV107490716; COSMIC: COSV107490716;