Genetic Variant SLC12A6:p.Arg675Gly (chr15-34243993-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001365088.1(SLC12A6):c.2023C>G(p.Arg675Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R675R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SLC12A6
NM_001365088.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.08

Publications

0 publications found

Variant links:

Genes affected

SLC12A6 (HGNC:10914): (solute carrier family 12 member 6) This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

SLC12A6 Gene-Disease associations (from GenCC):

agenesis of the corpus callosum with peripheral neuropathy
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Orphanet
Charcot-Marie-Tooth disease, axonal, IIa 2II
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

SLC12A6 links:

LOC124903461 (HGNC:):

LOC124903461 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001365088.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365088.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A6	NM_001365088.1	MANE Select	c.2023C>G	p.Arg675Gly	missense	Exon 16 of 26	NP_001352017.1	Q9UHW9-1
SLC12A6	NM_133647.2		c.2023C>G	p.Arg675Gly	missense	Exon 15 of 25	NP_598408.1	Q9UHW9-1
SLC12A6	NM_001042496.2		c.1996C>G	p.Arg666Gly	missense	Exon 16 of 26	NP_001035961.1	Q9UHW9-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.2023C>G	p.Arg675Gly	missense	Exon 16 of 26	ENSP00000346112.3	Q9UHW9-1
SLC12A6	ENST00000560611.5	TSL:1	c.2023C>G	p.Arg675Gly	missense	Exon 15 of 25	ENSP00000454168.1	Q9UHW9-1
SLC12A6	ENST00000558589.5	TSL:1	c.1996C>G	p.Arg666Gly	missense	Exon 16 of 26	ENSP00000452776.1	Q9UHW9-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

PhyloP100

4.1

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.87

Sift

Benign

0.056

Sift4G

Benign

0.065

Polyphen

0.97

Vest4

0.82

MutPred

0.77

Loss of methylation at R675 (P = 0.0288)

MVP

0.89

MPC

2.5

ClinPred

0.97

GERP RS

3.9

Varity_R

0.82

gMVP

0.85

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over