4-169660435-A-T

Position:

• chr4-169660435-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001243374.2(CLCN3):​c.66A>T​(p.Glu22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,377,732 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CLCN3 NM_001243374.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.138

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• 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 5.2004 (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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010869622).
• BP6: Variant 4-169660435-A-T is Benign according to our data. Variant chr4-169660435-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3351696.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN3	NM_001829.4	c.161-19615A>T		intron_variant		ENST00000513761.6	NP_001820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN3	ENST00000513761.6	c.161-19615A>T		intron_variant		1	NM_001829.4	ENSP00000424603.1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000725 AC: 26 AN: 35852 Hom.: 0 AF XY: 0.000734 AC XY: 15 AN XY: 20440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00178

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000343

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.000944

Gnomad OTH exome AF: 0.000967

GnomAD4 exome AF: 0.00128 AC: 1565 AN: 1225458 Hom.: 2 Cov.: 27 AF XY: 0.00119 AC XY: 711 AN XY: 599680

Gnomad4 AFR exome AF: 0.000159

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000534

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000802

Gnomad4 FIN exome AF: 0.000682

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000655

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74454

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000776 Hom.: 1

Bravo AF: 0.000759

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.000510 AC: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CLCN3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.80	T
PROVEAN	Benign	0.37	N;.
REVEL	Benign	0.19
Sift	Benign	0.28	T;.
Sift4G	Benign	0.85	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.11		Gain of glycosylation at S17 (P = 0.0592);Gain of glycosylation at S17 (P = 0.0592);
MVP		0.37
ClinPred		0.051	T
GERP RS		2.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs191793461; hg19: chr4-170581586;