NM_001287.6:c.141+3090C>T

Variant names:

• chr16-1471744-G-A
• rs1033466
• NM_001287.6:c.141+3090C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001287.6(CLCN7):​c.141+3090C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,180 control chromosomes in the GnomAD database, including 9,767 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9767 hom., cov: 33)
  • Exomes 𝑓: 0.19 (0 hom.)
• Consequence: CLCN7 NM_001287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.821
• Publications: 8 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

ENSG00000261430 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.521 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.141+3090C>T		intron	N/A	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.141+3090C>T		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.141+3090C>T		intron	N/A	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000569851.6	TSL:5	c.-154C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000461009.1	I3L470
	CLCN7	ENST00000569851.6	TSL:5	c.-154C>T		5_prime_UTR	Exon 1 of 9	ENSP00000461009.1	I3L470

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51462 AN: 152014 Hom.: 9742 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.319

GnomAD4 exome AF: 0.188 AC: 9 AN: 48 Hom.: 0 Cov.: 0 AF XY: 0.100 AC XY: 3 AN XY: 30

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.125 AC: 1 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.176 AC: 6 AN: 34

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.339 AC: 51538 AN: 152132 Hom.: 9767 Cov.: 33 AF XY: 0.341 AC XY: 25395 AN XY: 74388

African (AFR) AF: 0.496 AC: 20569 AN: 41476

American (AMR) AF: 0.293 AC: 4478 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1035 AN: 3468

East Asian (EAS) AF: 0.537 AC: 2777 AN: 5168

South Asian (SAS) AF: 0.343 AC: 1656 AN: 4826

European-Finnish (FIN) AF: 0.257 AC: 2723 AN: 10598

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17185 AN: 68000

Other (OTH) AF: 0.318 AC: 671 AN: 2110

Alfa AF: 0.275 Hom.: 10420

Bravo AF: 0.347

Asia WGS AF: 0.464 AC: 1612 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.84
PhyloP100		-0.82
PromoterAI		-0.0099	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: rs1033466; hg19: chr16-1521745;