15-48251770-GAT-CAC

Variant names:

• chr15-48251770-GGT-CAC
• NM_000338.3:c.1942_1942+2delGGTinsCAC
• SLC12A1 p.Asp648His

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000338.3(SLC12A1):​c.1942_1942+2delGGTinsCAC​(p.Asp648His) variant causes a splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D648N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A1 NM_000338.3 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.99
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.047272727 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.2, offset of -12, new splice context is: cttGTaaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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.1942_1942+2delGGTinsCAC	p.Asp648His	splice_donor missense splice_region intron	N/A	NP_000329.2	Q13621-1
	SLC12A1	NM_001184832.2		c.1942_1942+2delGGTinsCAC	p.Asp648His	splice_donor missense splice_region intron	N/A	NP_001171761.1	Q13621-3
	SLC12A1	NM_001384136.1		c.1942_1942+2delGGTinsCAC	p.Asp648His	splice_donor missense splice_region intron	N/A	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.1942_1942+2delGGTinsCAC	p.Asp648His	splice_donor missense splice_region intron	N/A	ENSP00000370381.3	Q13621-1
	SLC12A1	ENST00000558252.5	TSL:1	n.6065_6065+2delGGTinsCAC		splice_donor splice_region intron non_coding_transcript_exon	Exon 11 of 23
	SLC12A1	ENST00000560692.5	TSL:1	n.6081_6081+2delGGTinsCAC		splice_donor splice_region intron non_coding_transcript_exon	Exon 10 of 22

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-48543967;