chr4-169690542-T-G

Position:

chr4-169690542-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001829.4(CLCN3):c.619T>G(p.Tyr207Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CLCN3
NM_001829.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.84

Variant links:

Genes affected

CLCN3 (HGNC:2021): (chloride voltage-gated channel 3) This gene encodes a member of the voltage-gated chloride channel (ClC) family. The encoded protein is present in all cell types and localized in plasma membranes and in intracellular vesicles. It is a multi-pass membrane protein which contains a ClC domain and two additional C-terminal CBS (cystathionine beta-synthase) domains. The ClC domain catalyzes the selective flow of Cl- ions across cell membranes, and the CBS domain may have a regulatory function. This protein plays a role in both acidification and transmitter loading of GABAergic synaptic vesicles, and in smooth muscle cell activation and neointima formation. This protein is required for lysophosphatidic acid (LPA)-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. The protein activity is regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in glioma cells. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

CLCN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CLCN3. . Gene score misZ 4.3745 (greater than the threshold 3.09). Trascript score misZ 5.1954 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with seizures and brain abnormalities, complex neurodevelopmental disorder, neurodevelopmental disorder with hypotonia and brain abnormalities.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN3	NM_001829.4 linkuse as main transcript	c.619T>G	p.Tyr207Asp	missense_variant	6/13	ENST00000513761.6	NP_001820.2	P51790-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLCN3	ENST00000513761.6 linkuse as main transcript	c.619T>G	p.Tyr207Asp	missense_variant	6/13	1	NM_001829.4	ENSP00000424603.1	P51790-1
CLCN3	ENST00000347613.9 linkuse as main transcript	c.619T>G	p.Tyr207Asp	missense_variant	6/14	1		ENSP00000261514.5	P51790-2
CLCN3	ENST00000360642.7 linkuse as main transcript	c.619T>G	p.Tyr207Asp	missense_variant	6/12	2		ENSP00000353857.3	P51790-4
CLCN3	ENST00000507875.6 linkuse as main transcript	c.538T>G	p.Tyr180Asp	missense_variant	5/12	2		ENSP00000425323.2	E9PE15

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

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

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248414

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS 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:

6.86e-7

AC:

AN:

1458746

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725570

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.619T>G (p.Y207D) alteration is located in exon 1 (coding exon 1) of the CLCN3 gene. This alteration results from a T to G substitution at nucleotide position 619, causing the tyrosine (Y) at amino acid position 207 to be replaced by an aspartic acid (D). 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

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

D;.;.;.;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.1

M;M;M;.;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-9.3

D;D;D;D;.;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;D;D;D;.;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

0.23

B;B;.;D;.;.

Vest4

0.89

MutPred

0.57

Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);.;.;.;

MVP

0.99

MPC

2.6

ClinPred

1.0

GERP RS

5.4

Varity_R

0.91

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over