ENST00000185206.12:c.340A>C

Variant names:

• chr6-46079903-T-G
• rs723580
• ENST00000185206.12:c.340A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000185206.12(CLIC5):​c.340A>C​(p.Thr114Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T114A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLIC5 ENST00000185206.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.780
• Publications: 12 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06345454).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000185206.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC5	NM_001114086.2		c.340A>C	p.Thr114Pro	missense	Exon 1 of 6	NP_001107558.1
	CLIC5	NM_001370650.1		c.340A>C	p.Thr114Pro	missense	Exon 2 of 7	NP_001357579.1
	CLIC5	NM_001370649.1		c.-55+49601A>C		intron	N/A	NP_001357578.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC5	ENST00000185206.12	TSL:1	c.340A>C	p.Thr114Pro	missense	Exon 1 of 6	ENSP00000185206.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 415

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.065
DANN	Benign	0.66
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.78
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.0080
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.057
MutPred		0.087		Loss of phosphorylation at T114 (P = 0.0321)
MVP		0.055
MPC		0.15
ClinPred		0.13	T
GERP RS		-9.3
PromoterAI		0.0042	Neutral
Varity_R		0.091
gMVP		0.14
Mutation Taster		=97/3	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs723580; hg19: chr6-46047640;