20-46021799-C-A

Variant names:

• chr20-46021799-C-A
• rs2145463602
• NM_001134771.2:c.34C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134771.2(SLC12A5):​c.34C>A​(p.Pro12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,380,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. P12A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SLC12A5 NM_001134771.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0520
• Publications: 0 publications found

Genes affected

SLC12A5 (HGNC:13818): (solute carrier family 12 member 5) K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]

SLC12A5-AS1 (HGNC:53143): (SLC12A5 and MMP9 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089487046).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134771.2. 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
	SLC12A5	NM_001134771.2		c.34C>A	p.Pro12Thr	missense	Exon 1 of 26	NP_001128243.1	Q9H2X9-1
	SLC12A5-AS1	NR_147699.1		n.275G>T		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000454036.6	TSL:5	c.34C>A	p.Pro12Thr	missense	Exon 1 of 26	ENSP00000387694.1	Q9H2X9-1
	SLC12A5	ENST00000626701.1	TSL:3	c.34C>A	p.Pro12Thr	missense	Exon 1 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000628272.1	TSL:3	c.34C>A	p.Pro12Thr	missense	Exon 1 of 2	ENSP00000486382.1	A0A0D9SF89

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1380986 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 681618

African (AFR) AF: 0.00 AC: 0 AN: 31152

American (AMR) AF: 0.00 AC: 0 AN: 35632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.00 AC: 0 AN: 35512

South Asian (SAS) AF: 0.00 AC: 0 AN: 79068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4468

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1078018

Other (OTH) AF: 0.00 AC: 0 AN: 57680

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.052
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.13
Sift	Benign	0.53	T
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.098
MutPred		0.20		Gain of sheet (P = 0.0085)
MVP		0.47
MPC		1.1
ClinPred		0.099	T
GERP RS		2.5
PromoterAI		0.017	Neutral
Varity_R		0.034
gMVP		0.28
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2145463602; hg19: chr20-44650438;