rs16985442

Positions:

• chr20-46043236-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_020708.5(SLC12A5):​c.1150C>G​(p.Pro384Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,613,800 control chromosomes in the GnomAD database, including 1,903 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.046 (199 hom., cov: 31)
  • Exomes 𝑓: 0.046 (1704 hom.)
• Consequence: SLC12A5 NM_020708.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.668

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC12A5. . Gene score misZ 4.7022 (greater than the threshold 3.09). Trascript score misZ 6.2616 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 34, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, epilepsy, idiopathic generalized, susceptibility to, 14.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025883317).
• BP6: Variant 20-46043236-C-G is Benign according to our data. Variant chr20-46043236-C-G is described in ClinVar as [Benign]. Clinvar id is 475639.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0456 (6929/151952) while in subpopulation NFE AF= 0.0489 (3322/67932). AF 95% confidence interval is 0.0475. There are 199 homozygotes in gnomad4. There are 3493 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 199 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5	NM_020708.5	c.1150C>G	p.Pro384Ala	missense_variant	9/26	ENST00000243964.7
SLC12A5	NM_001134771.2	c.1219C>G	p.Pro407Ala	missense_variant	9/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5	ENST00000243964.7	c.1150C>G	p.Pro384Ala	missense_variant	9/26	1	NM_020708.5	A1

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6927 AN: 151834 Hom.: 199 Cov.: 31

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00708

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0489

Gnomad OTH AF: 0.0465

GnomAD3 exomes AF: 0.0398 AC: 10005 AN: 251396 Hom.: 263 AF XY: 0.0396 AC XY: 5379 AN XY: 135878

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.0279

Gnomad ASJ exome AF: 0.0562

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00719

Gnomad FIN exome AF: 0.0952

Gnomad NFE exome AF: 0.0473

Gnomad OTH exome AF: 0.0441

GnomAD4 exome AF: 0.0456 AC: 66636 AN: 1461848 Hom.: 1704 Cov.: 32 AF XY: 0.0444 AC XY: 32289 AN XY: 727228

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.0302

Gnomad4 ASJ exome AF: 0.0584

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00699

Gnomad4 FIN exome AF: 0.0923

Gnomad4 NFE exome AF: 0.0487

Gnomad4 OTH exome AF: 0.0408

GnomAD4 genome AF: 0.0456 AC: 6929 AN: 151952 Hom.: 199 Cov.: 31 AF XY: 0.0470 AC XY: 3493 AN XY: 74290

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0591

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00688

Gnomad4 FIN AF: 0.0967

Gnomad4 NFE AF: 0.0489

Gnomad4 OTH AF: 0.0460

Alfa AF: 0.0489 Hom.: 69

Bravo AF: 0.0416

TwinsUK AF: 0.0483 AC: 179

ALSPAC AF: 0.0522 AC: 201

ESP6500AA AF: 0.0390 AC: 172

ESP6500EA AF: 0.0480 AC: 413

ExAC AF: 0.0383 AC: 4646

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0434

EpiControl AF: 0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 34 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N;.;N
REVEL	Benign	0.20
Sift	Uncertain	0.026	D;.;D
Sift4G	Benign	0.083	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.081
MPC		0.93
ClinPred		0.011	T
GERP RS		4.5
Varity_R		0.11
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

LitVar

Other links and lift over

dbSNP: rs16985442; hg19: chr20-44671875; COSMIC: COSV54793767; COSMIC: COSV54793767;