chr15-34250979-C-G

Variant names:

• chr15-34250979-C-G
• rs140916001
• NM_001365088.1:c.1412G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365088.1(SLC12A6):​c.1412G>C​(p.Ser471Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,610,528 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S471R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0087 (53 hom.)
• Consequence: SLC12A6 NM_001365088.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0430
• Publications: 5 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027124584).
• BP6: Variant 15-34250979-C-G is Benign according to our data. Variant chr15-34250979-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00531 (808/152196) while in subpopulation NFE AF = 0.00891 (606/68002). AF 95% confidence interval is 0.00832. There are 4 homozygotes in GnomAd4. There are 355 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	NM_001365088.1	MANE Select	c.1412G>C	p.Ser471Thr	missense	Exon 11 of 26	NP_001352017.1	Q9UHW9-1
	SLC12A6	NM_133647.2		c.1412G>C	p.Ser471Thr	missense	Exon 10 of 25	NP_598408.1	Q9UHW9-1
	SLC12A6	NM_001042496.2		c.1385G>C	p.Ser462Thr	missense	Exon 11 of 26	NP_001035961.1	Q9UHW9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.1412G>C	p.Ser471Thr	missense	Exon 11 of 26	ENSP00000346112.3	Q9UHW9-1
	SLC12A6	ENST00000560611.5	TSL:1	c.1412G>C	p.Ser471Thr	missense	Exon 10 of 25	ENSP00000454168.1	Q9UHW9-1
	SLC12A6	ENST00000558589.5	TSL:1	c.1385G>C	p.Ser462Thr	missense	Exon 11 of 26	ENSP00000452776.1	Q9UHW9-4

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 809 AN: 152078 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00893

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00584 AC: 1468 AN: 251476 AF XY: 0.00592

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00999

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.00868 AC: 12654 AN: 1458332 Hom.: 53 Cov.: 32 AF XY: 0.00845 AC XY: 6136 AN XY: 725786

African (AFR) AF: 0.00156 AC: 52 AN: 33412

American (AMR) AF: 0.00394 AC: 176 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00678 AC: 177 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000847 AC: 73 AN: 86194

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53420

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5764

European-Non Finnish (NFE) AF: 0.0104 AC: 11476 AN: 1108758

Other (OTH) AF: 0.00951 AC: 573 AN: 60268

GnomAD4 genome AF: 0.00531 AC: 808 AN: 152196 Hom.: 4 Cov.: 31 AF XY: 0.00477 AC XY: 355 AN XY: 74394

African (AFR) AF: 0.00169 AC: 70 AN: 41540

American (AMR) AF: 0.00380 AC: 58 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00227 AC: 24 AN: 10586

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00891 AC: 606 AN: 68002

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00834 Hom.: 5

Bravo AF: 0.00530

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00602 AC: 731

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.00901

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	4	Agenesis of the corpus callosum with peripheral neuropathy (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.043
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.14
Sift	Benign	0.44	T
Sift4G	Benign	0.66	T
Polyphen		0.0010	B
Vest4		0.063
MVP		0.24
MPC		0.29
ClinPred		0.0012	T
GERP RS		-0.25
Varity_R		0.028
gMVP		0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140916001; hg19: chr15-34543180; COSMIC: COSV99063249; COSMIC: COSV99063249;