rs3729618

Variant names:

• chr6-45920336-A-G
• rs3729618
• NM_016929.5:c.407-5927T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-45920336-A-G
• chr6-45920336-A-T

Variant summary

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

The NM_016929.5(CLIC5):​c.407-5927T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 943,144 control chromosomes in the GnomAD database, including 43,737 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 0.27 (5932 hom., cov: 32)
  • Exomes 𝑓: 0.30 (37805 hom.)
• Consequence: CLIC5 NM_016929.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.340
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

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.407-5927T>C		intron	N/A	NP_058625.2	Q53G01
	CLIC5	NM_001114086.2		c.884-5927T>C		intron	N/A	NP_001107558.1	Q9NZA1-1
	CLIC5	NM_001370650.1		c.884-5927T>C		intron	N/A	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.407-5927T>C		intron	N/A	ENSP00000344165.6	Q9NZA1-2
	CLIC5	ENST00000185206.12	TSL:1	c.884-5927T>C		intron	N/A	ENSP00000185206.6	Q9NZA1-1
	CLIC5	ENST00000644324.1		c.407-5927T>C		intron	N/A	ENSP00000495186.1	A0A2R8Y615

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41202 AN: 151990 Hom.: 5931 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.301 AC: 238426 AN: 791036 Hom.: 37805 Cov.: 15 AF XY: 0.303 AC XY: 110735 AN XY: 365728

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.159 AC: 2436 AN: 15304

American (AMR) AF: 0.193 AC: 181 AN: 938

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1588 AN: 4892

East Asian (EAS) AF: 0.456 AC: 1557 AN: 3414

South Asian (SAS) AF: 0.336 AC: 5227 AN: 15566

European-Finnish (FIN) AF: 0.268 AC: 68 AN: 254

Middle Eastern (MID) AF: 0.313 AC: 487 AN: 1558

European-Non Finnish (NFE) AF: 0.303 AC: 219049 AN: 723148

Other (OTH) AF: 0.302 AC: 7833 AN: 25962

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.271 AC: 41211 AN: 152108 Hom.: 5932 Cov.: 32 AF XY: 0.271 AC XY: 20180 AN XY: 74354

African (AFR) AF: 0.183 AC: 7579 AN: 41504

American (AMR) AF: 0.229 AC: 3499 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1127 AN: 3470

East Asian (EAS) AF: 0.477 AC: 2460 AN: 5158

South Asian (SAS) AF: 0.371 AC: 1790 AN: 4822

European-Finnish (FIN) AF: 0.269 AC: 2843 AN: 10576

Middle Eastern (MID) AF: 0.266 AC: 77 AN: 290

European-Non Finnish (NFE) AF: 0.309 AC: 21015 AN: 67966

Other (OTH) AF: 0.284 AC: 601 AN: 2116

Alfa AF: 0.270 Hom.: 972

Bravo AF: 0.262

Asia WGS AF: 0.415 AC: 1442 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.56
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3729618; hg19: chr6-45888073;