rs12926089

chr16-1452856-C-Achr16-1452856-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001287.6(CLCN7):c.1252G>T(p.Val418Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V418M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCN7 NM_001287.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.787

Genes affected

CLCN7 (HGNC:2025): (chloride voltage-gated channel 7) The product of this gene belongs to the CLC chloride channel family of proteins. Chloride channels play important roles in the plasma membrane and in intracellular organelles. This gene encodes chloride channel 7. Defects in this gene are the cause of osteopetrosis autosomal recessive type 4 (OPTB4), also called infantile malignant osteopetrosis type 2 as well as the cause of autosomal dominant osteopetrosis type 2 (OPTA2), also called autosomal dominant Albers-Schonberg disease or marble disease autosoml dominant. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. OPTA2 is the most common form of osteopetrosis, occurring in adolescence or adulthood. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11705476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN7	NM_001287.6	c.1252G>T	p.Val418Leu	missense_variant	15/25	ENST00000382745.9
CLCN7	NM_001114331.3	c.1180G>T	p.Val394Leu	missense_variant	14/24
CLCN7	XM_011522354.2	c.1078G>T	p.Val360Leu	missense_variant	15/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9	c.1252G>T	p.Val418Leu	missense_variant	15/25	1	NM_001287.6	P1
CLCN7	ENST00000262318.12	c.1180G>T	p.Val394Leu	missense_variant	14/24	5
CLCN7	ENST00000699947.1	c.1252G>T	p.Val418Leu	missense_variant	15/25
CLCN7	ENST00000699948.1	c.1252G>T	p.Val418Leu	missense_variant, NMD_transcript_variant	15/25

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1427480 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707278

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	16
Dann	Benign	0.65
DEOGEN2	Uncertain	0.42	T;.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.24	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.98	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.24
MutPred		0.63		Loss of catalytic residue at V418 (P = 0.0725);.;.;
MVP		0.18
MPC		0.57
ClinPred		0.12	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.64

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: rs12926089; hg19: chr16-1502857;