chr6-45903184-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016929.5(CLIC5):​c.660C>G​(p.Asn220Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,436 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N220N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CLIC5 NM_016929.5 missense
• Clinical Significance: Not reported in ClinVar
• 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):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 103

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>G	p.Asn220Lys	missense	Exon 6 of 6	NP_058625.2	Q53G01
	CLIC5	NM_001114086.2		c.1137C>G	p.Asn379Lys	missense	Exon 6 of 6	NP_001107558.1	Q9NZA1-1
	CLIC5	NM_001370650.1		c.1137C>G	p.Asn379Lys	missense	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>G	p.Asn220Lys	missense	Exon 6 of 6	ENSP00000344165.6	Q9NZA1-2
	CLIC5	ENST00000185206.12	TSL:1	c.1137C>G	p.Asn379Lys	missense	Exon 6 of 6	ENSP00000185206.6	Q9NZA1-1
	CLIC5	ENST00000644324.1		c.623+10594C>G		intron	N/A	ENSP00000495186.1	A0A2R8Y615

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461260 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726926

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00000630 AC: 7 AN: 1111792

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.0061	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.9
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.9	L
PhyloP100		-0.079
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.50
Sift	Benign	0.036	D
Sift4G	Uncertain	0.054	T
Polyphen		0.99	D
Vest4		0.43
MutPred		0.51		Gain of MoRF binding (P = 0.0377)
MVP		0.95
MPC		0.56
ClinPred		1.0	D
GERP RS		-7.6
Varity_R		0.79
gMVP		0.61
Mutation Taster		=42/58	disease causing

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;