20-46021773-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NR_147699.1(SLC12A5-AS1):n.301C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,380,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC12A5-AS1 NR_147699.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

Genes affected

SLC12A5-AS1 (HGNC:53143): (SLC12A5 and MMP9 antisense RNA 1)

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18408999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5-AS1	NR_147699.1	n.301C>T		non_coding_transcript_exon_variant	1/3
SLC12A5	NM_001134771.2	c.8G>A	p.Arg3His	missense_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5-AS1	ENST00000535913.2	n.301C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1380962 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 681738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2020

The c.8G>A (p.R3H) alteration is located in exon 1 (coding exon 1) of the SLC12A5 gene. This alteration results from a G to A substitution at nucleotide position 8, causing the arginine (R) at amino acid position 3 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.069	T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.11	N;.;.
REVEL	Benign	0.26
Sift	Benign	0.15	T;.;.
Sift4G	Benign	0.16	T;D;D
Polyphen		0.23	B;.;.
Vest4		0.20
MutPred		0.20		Loss of MoRF binding (P = 0.0146);Loss of MoRF binding (P = 0.0146);Loss of MoRF binding (P = 0.0146);
MVP		0.62
MPC		1.2
ClinPred		0.50	D
GERP RS		4.6
Varity_R		0.13
gMVP		0.25

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1423123160; hg19: chr20-44650412;