rs16985442

Variant names:

• chr20-46043236-C-G
• rs16985442
• NM_020708.5:c.1150C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 16/21 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.668
• Publications: 15 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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 34

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• epilepsy of infancy with migrating focal seizures

  Inheritance: AR Classification: STRONG Submitted by: G2P
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 14

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, PanelApp Australia, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• 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 VariationId is 475639.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 = 0.0456 (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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 199 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020708.5. 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_020708.5	MANE Select	c.1150C>G	p.Pro384Ala	missense	Exon 9 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.1219C>G	p.Pro407Ala	missense	Exon 9 of 26	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.1150C>G	p.Pro384Ala	missense	Exon 9 of 26	ENSP00000243964.4	Q9H2X9-2
	SLC12A5	ENST00000616202.4	TSL:1	c.612+5851C>G		intron	N/A	ENSP00000478369.1	M4PM71
	SLC12A5	ENST00000626937.2	TSL:1	c.509+5954C>G		intron	N/A	ENSP00000485953.1	M4PNC0

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

GnomAD2 exomes AF: 0.0398 AC: 10005 AN: 251396 AF XY: 0.0396

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 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

African (AFR) AF: 0.0384 AC: 1287 AN: 33480

American (AMR) AF: 0.0302 AC: 1349 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 1525 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.00699 AC: 603 AN: 86256

European-Finnish (FIN) AF: 0.0923 AC: 4928 AN: 53416

Middle Eastern (MID) AF: 0.0499 AC: 288 AN: 5768

European-Non Finnish (NFE) AF: 0.0487 AC: 54186 AN: 1111982

Other (OTH) AF: 0.0408 AC: 2465 AN: 60396

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

African (AFR) AF: 0.0364 AC: 1508 AN: 41428

American (AMR) AF: 0.0423 AC: 646 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 205 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00688 AC: 33 AN: 4798

European-Finnish (FIN) AF: 0.0967 AC: 1023 AN: 10580

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0489 AC: 3322 AN: 67932

Other (OTH) AF: 0.0460 AC: 97 AN: 2108

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 34 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.67
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Uncertain	0.026	D
Sift4G	Benign	0.083	T
Polyphen		0.0	B
Vest4		0.081
MPC		0.93
ClinPred		0.011	T
GERP RS		4.5
Varity_R		0.11
gMVP		0.85
Mutation Taster		=91/9	polymorphism (auto)

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