chr16-1448407-G-A

Variant names:

• chr16-1448407-G-A
• rs114827619
• NM_001287.6:c.1961C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001287.6(CLCN7):​c.1961C>T​(p.Thr654Met) variant causes a missense change. The variant allele was found at a frequency of 0.000854 in 1,612,678 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T654T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00047 (6 hom.)
• Consequence: CLCN7 NM_001287.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.55
• Publications: 3 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 (MetaRNN=0.006703049).
• BP6: Variant 16-1448407-G-A is Benign according to our data. Variant chr16-1448407-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00452 (689/152324) while in subpopulation AFR AF = 0.0156 (650/41570). AF 95% confidence interval is 0.0146. There are 2 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD gene

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.1961C>T	p.Thr654Met	missense	Exon 21 of 25	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.1889C>T	p.Thr630Met	missense	Exon 20 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.1961C>T	p.Thr654Met	missense	Exon 21 of 25	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.1889C>T	p.Thr630Met	missense	Exon 20 of 24	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.2042C>T	p.Thr681Met	missense	Exon 21 of 25	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152206 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00117 AC: 292 AN: 249498 AF XY: 0.000864

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.000900

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000800

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000471 AC: 688 AN: 1460354 Hom.: 6 Cov.: 31 AF XY: 0.000403 AC XY: 293 AN XY: 726458

African (AFR) AF: 0.0151 AC: 505 AN: 33480

American (AMR) AF: 0.000984 AC: 44 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51998

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111940

Other (OTH) AF: 0.00104 AC: 63 AN: 60372

GnomAD4 genome AF: 0.00452 AC: 689 AN: 152324 Hom.: 2 Cov.: 34 AF XY: 0.00432 AC XY: 322 AN XY: 74478

African (AFR) AF: 0.0156 AC: 650 AN: 41570

American (AMR) AF: 0.00118 AC: 18 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00218 Hom.: 6

Bravo AF: 0.00512

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0067	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.54
Sift	Benign	0.035	D
Sift4G	Benign	0.072	T
Polyphen		0.95	P
Vest4		0.58
MVP		0.86
MPC		0.73
ClinPred		0.046	T
GERP RS		4.2
Varity_R		0.058
gMVP		0.74
Mutation Taster		=87/13	polymorphism

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: rs114827619; hg19: chr16-1498408;