chr16-1451374-G-T

Variant names:

• chr16-1451374-G-T
• rs8045185
• NM_001287.6:c.1447+249C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001287.6(CLCN7):​c.1447+249C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,042 control chromosomes in the GnomAD database, including 19,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (19438 hom., cov: 33)
• Consequence: CLCN7 NM_001287.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.29
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 16-1451374-G-T is Benign according to our data. Variant chr16-1451374-G-T is described in ClinVar as Benign. ClinVar VariationId is 1254171.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 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.1447+249C>A		intron	N/A	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.1375+249C>A		intron	N/A	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.1447+249C>A		intron	N/A	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.1375+249C>A		intron	N/A	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.1528+249C>A		intron	N/A	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76157 AN: 151924 Hom.: 19412 Cov.: 33

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.506

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.501 AC: 76231 AN: 152042 Hom.: 19438 Cov.: 33 AF XY: 0.500 AC XY: 37165 AN XY: 74328

African (AFR) AF: 0.490 AC: 20332 AN: 41458

American (AMR) AF: 0.510 AC: 7801 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1553 AN: 3466

East Asian (EAS) AF: 0.775 AC: 4017 AN: 5182

South Asian (SAS) AF: 0.505 AC: 2431 AN: 4814

European-Finnish (FIN) AF: 0.467 AC: 4947 AN: 10582

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.492 AC: 33437 AN: 67936

Other (OTH) AF: 0.504 AC: 1066 AN: 2114

Alfa AF: 0.496 Hom.: 23798

Bravo AF: 0.510

Asia WGS AF: 0.613 AC: 2128 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.19
DANN	Benign	0.44
PhyloP100		-3.3
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: rs8045185; hg19: chr16-1501375; COSMIC: COSV51975028; COSMIC: COSV51975028;