chr6-45903184-G-A

Variant names:

• chr6-45903184-G-A
• rs138583424
• NM_016929.5:c.660C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_016929.5(CLIC5):​c.660C>T​(p.Asn220Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: CLIC5 NM_016929.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0790
• Publications: 3 publications found

Genes affected

CLIC5 (HGNC:13517): (chloride intracellular channel 5) This gene encodes a member of the chloride intracellular channel (CLIC) family of chloride ion channels. The encoded protein associates with actin-based cytoskeletal structures and may play a role in multiple processes including hair cell stereocilia formation, myoblast proliferation and glomerular podocyte and endothelial cell maintenance. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

CLIC5 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 103

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-45903184-G-A is Benign according to our data. Variant chr6-45903184-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3637049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.079 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016929.5. 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
	CLIC5	NM_016929.5	MANE Select	c.660C>T	p.Asn220Asn	synonymous	Exon 6 of 6	NP_058625.2	Q53G01
	CLIC5	NM_001114086.2		c.1137C>T	p.Asn379Asn	synonymous	Exon 6 of 6	NP_001107558.1	Q9NZA1-1
	CLIC5	NM_001370650.1		c.1137C>T	p.Asn379Asn	synonymous	Exon 7 of 7	NP_001357579.1	Q9NZA1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC5	ENST00000339561.12	TSL:1 MANE Select	c.660C>T	p.Asn220Asn	synonymous	Exon 6 of 6	ENSP00000344165.6	Q9NZA1-2
	CLIC5	ENST00000185206.12	TSL:1	c.1137C>T	p.Asn379Asn	synonymous	Exon 6 of 6	ENSP00000185206.6	Q9NZA1-1
	CLIC5	ENST00000644324.1		c.623+10594C>T		intron	N/A	ENSP00000495186.1	A0A2R8Y615

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000761 AC: 19 AN: 249694 AF XY: 0.0000889

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000976

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461258 Hom.: 0 Cov.: 30 AF XY: 0.0000605 AC XY: 44 AN XY: 726926

African (AFR) AF: 0.000120 AC: 4 AN: 33428

American (AMR) AF: 0.0000673 AC: 3 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000738 AC: 82 AN: 1111792

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74466

African (AFR) AF: 0.000192 AC: 8 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.000327

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.46
CADD	Benign	2.5
DANN	Benign	0.73
PhyloP100		-0.079
Mutation Taster		=100/0	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: rs138583424; hg19: chr6-45870921; COSMIC: COSV51756387;