NM_020708.5:c.2376T>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP7BS1

The NM_020708.5(SLC12A5):c.2376T>A(p.Ile792Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I792I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000087 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

SLC12A5
NM_020708.5 splice_region, synonymous

Scores

Splicing: ADA: 0.0001043

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.12

Publications

0 publications found

Variant links:

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

SLC12A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP7

Synonymous conserved (PhyloP=-3.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000183 (2/1092710) while in subpopulation AFR AF = 0.0000922 (2/21686). AF 95% confidence interval is 0.0000163. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.2376T>A	p.Ile792Ile	splice_region synonymous	Exon 18 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.2445T>A	p.Ile815Ile	splice_region synonymous	Exon 18 of 26	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.2376T>A	p.Ile792Ile	splice_region synonymous	Exon 18 of 26	ENSP00000243964.4	Q9H2X9-2
SLC12A5	ENST00000616202.4	TSL:1	c.613-6612T>A		intron	N/A	ENSP00000478369.1	M4PM71
SLC12A5	ENST00000626937.2	TSL:1	c.510-7730T>A		intron	N/A	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes

AF:

0.00000867

AC:

AN:

115376

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000337

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000530

AC:

AN:

188656

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000844

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1092710

Hom.:

Cov.:

AF XY:

0.00000369

AC XY:

AN XY:

541464

show subpopulations

African (AFR)

AF:

0.0000922

AC:

AN:

21686

American (AMR)

AF:

0.00

AC:

AN:

26728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16610

East Asian (EAS)

AF:

0.00

AC:

AN:

14662

South Asian (SAS)

AF:

0.00

AC:

AN:

72606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4400

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

863668

Other (OTH)

AF:

0.00

AC:

AN:

41368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000867

AC:

AN:

115376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

52758

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000337

AC:

AN:

29690

American (AMR)

AF:

0.00

AC:

AN:

8332

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3226

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00

AC:

AN:

3476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

224

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60434

Other (OTH)

AF:

0.00

AC:

AN:

1586

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.25

(source)

DANN

Benign

0.67

PhyloP100

-3.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.096

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over