rs3848724

Variant names:

• chr20-46035852-C-A
• rs3848724
• NM_020708.5:c.355C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-46035852-C-A
• chr20-46035852-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020708.5(SLC12A5):​c.355C>A​(p.Arg119Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,614,082 control chromosomes in the GnomAD database, including 1,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R119R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.029 (173 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1016 hom.)
• Consequence: SLC12A5 NM_020708.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.61
• Publications: 10 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: 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, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 20-46035852-C-A is Benign according to our data. Variant chr20-46035852-C-A is described in ClinVar as Benign. ClinVar VariationId is 475656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_020708.5	MANE Select	c.355C>A	p.Arg119Arg	synonymous	Exon 4 of 26	NP_065759.1
	SLC12A5	NM_001134771.2		c.424C>A	p.Arg142Arg	synonymous	Exon 4 of 26	NP_001128243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.355C>A	p.Arg119Arg	synonymous	Exon 4 of 26	ENSP00000243964.4
	SLC12A5	ENST00000616202.4	TSL:1	c.355C>A	p.Arg119Arg	synonymous	Exon 4 of 7	ENSP00000478369.1
	SLC12A5	ENST00000626937.2	TSL:1	c.355C>A	p.Arg119Arg	synonymous	Exon 4 of 7	ENSP00000485953.1

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4428 AN: 152238 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.00799

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.0283

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0340

GnomAD2 exomes AF: 0.0414 AC: 10390 AN: 251198 AF XY: 0.0373

Gnomad AFR exome AF: 0.00572

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.0513

Gnomad EAS exome AF: 0.0293

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0275 AC: 40179 AN: 1461728 Hom.: 1016 Cov.: 32 AF XY: 0.0272 AC XY: 19774 AN XY: 727182

African (AFR) AF: 0.00517 AC: 173 AN: 33480

American (AMR) AF: 0.150 AC: 6691 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0529 AC: 1381 AN: 26120

East Asian (EAS) AF: 0.0354 AC: 1404 AN: 39696

South Asian (SAS) AF: 0.0299 AC: 2578 AN: 86244

European-Finnish (FIN) AF: 0.0193 AC: 1033 AN: 53412

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5764

European-Non Finnish (NFE) AF: 0.0225 AC: 25038 AN: 1111938

Other (OTH) AF: 0.0298 AC: 1797 AN: 60384

GnomAD4 genome AF: 0.0291 AC: 4433 AN: 152354 Hom.: 173 Cov.: 32 AF XY: 0.0309 AC XY: 2301 AN XY: 74510

African (AFR) AF: 0.00796 AC: 331 AN: 41572

American (AMR) AF: 0.118 AC: 1810 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 187 AN: 3468

East Asian (EAS) AF: 0.0281 AC: 146 AN: 5190

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4830

European-Finnish (FIN) AF: 0.0184 AC: 196 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0223 AC: 1520 AN: 68036

Other (OTH) AF: 0.0346 AC: 73 AN: 2112

Alfa AF: 0.0251 Hom.: 109

Bravo AF: 0.0349

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.0231

EpiControl AF: 0.0244

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 34 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.7
DANN	Benign	0.65
PhyloP100		1.6
Mutation Taster		=95/5	polymorphism (auto)

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: rs3848724; hg19: chr20-44664491;