16-1445005-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: Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive osteopetrosis 4

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

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287.6. 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
	CLCN7	NM_001287.6	MANE Select	c.*1626G>C		3_prime_UTR	Exon 25 of 25	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.*1626G>C		3_prime_UTR	Exon 24 of 24	NP_001107803.1	P51798-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN7	ENST00000382745.9	TSL:1 MANE Select	c.*1626G>C		3_prime_UTR	Exon 25 of 25	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000892992.1		c.*1626G>C		3_prime_UTR	Exon 26 of 26	ENSP00000563051.1
	CLCN7	ENST00000892993.1		c.*1626G>C		3_prime_UTR	Exon 24 of 24	ENSP00000563052.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

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;