15-34252219-G-C

Variant names:

• chr15-34252219-G-C
• rs34098566
• NM_001365088.1:c.1284C>G

Variant summary

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

The NM_001365088.1(SLC12A6):​c.1284C>G​(p.Asn428Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N428N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A6 NM_001365088.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0380
• Publications: 2 publications found

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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease, axonal, IIa 2II

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A6	NM_001365088.1	c.1284C>G	p.Asn428Lys	missense_variant	Exon 10 of 26	ENST00000354181.8	NP_001352017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A6	ENST00000354181.8	c.1284C>G	p.Asn428Lys	missense_variant	Exon 10 of 26	1	NM_001365088.1	ENSP00000346112.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	.;.;D;D;.;.;T;D;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.97	D;D;.;.;.;D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.7	.;.;M;M;.;.;.;M;.
PhyloP100		-0.038
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T
Polyphen		0.72, 0.80, 0.057	.;P;P;P;.;.;B;P;.
Vest4		0.75
MutPred		0.68		.;.;Gain of methylation at N428 (P = 0.016);Gain of methylation at N428 (P = 0.016);.;.;.;Gain of methylation at N428 (P = 0.016);.;
MVP		0.57
MPC		0.68
ClinPred		0.96	D
GERP RS		-2.6
Varity_R		0.25
gMVP		0.93

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

Other links and lift over

dbSNP: rs34098566; hg19: chr15-34544420;