chr16-1445005-C-G

Variant names:

• chr16-1445005-C-G
• rs8767
• NM_001287.6:c.*1626G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001287.6(CLCN7):​c.*1626G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 152,226 control chromosomes in the GnomAD database, including 28,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28702 hom., cov: 34)
  • Exomes 𝑓: 0.67 (15 hom.)
• Consequence: CLCN7 NM_001287.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.56
• Publications: 6 publications found

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]

CLCN7 Gene-Disease associations (from GenCC):

• autosomal dominant osteopetrosis 2

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• autosomal recessive osteopetrosis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp, Ambry Genetics
• hypopigmentation, organomegaly, and delayed myelination and development

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• autosomal recessive osteopetrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive osteopetrosis 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-1445005-C-G is Benign according to our data. Variant chr16-1445005-C-G is described in ClinVar as Benign. ClinVar VariationId is 317904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN7	NM_001287.6	c.*1626G>C		3_prime_UTR_variant	Exon 25 of 25	ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3	c.*1626G>C		3_prime_UTR_variant	Exon 24 of 24		NP_001107803.1
CLCN7	XM_011522354.2	c.*1626G>C		3_prime_UTR_variant	Exon 25 of 25		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9	c.*1626G>C		3_prime_UTR_variant	Exon 25 of 25	1	NM_001287.6	ENSP00000372193.4
CLCN7	ENST00000563642.6	n.4113G>C		non_coding_transcript_exon_variant	Exon 9 of 9	2

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92528 AN: 152030 Hom.: 28664 Cov.: 34

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.612

GnomAD4 exome AF: 0.667 AC: 52 AN: 78 Hom.: 15 Cov.: 0 AF XY: 0.635 AC XY: 33 AN XY: 52

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.600 AC: 6 AN: 10

European-Finnish (FIN) AF: 0.833 AC: 5 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.643 AC: 36 AN: 56

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.609 AC: 92624 AN: 152148 Hom.: 28702 Cov.: 34 AF XY: 0.605 AC XY: 44952 AN XY: 74360

African (AFR) AF: 0.699 AC: 29005 AN: 41496

American (AMR) AF: 0.591 AC: 9028 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2189 AN: 3472

East Asian (EAS) AF: 0.813 AC: 4212 AN: 5178

South Asian (SAS) AF: 0.588 AC: 2838 AN: 4830

European-Finnish (FIN) AF: 0.498 AC: 5280 AN: 10594

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38042 AN: 67976

Other (OTH) AF: 0.610 AC: 1290 AN: 2116

Alfa AF: 0.416 Hom.: 953

Bravo AF: 0.624

Asia WGS AF: 0.668 AC: 2321 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Osteopetrosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.11
DANN	Benign	0.40
PhyloP100		-1.6
PromoterAI		-0.047	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8767; hg19: chr16-1495006;