Genetic Variant CHIC2:p.Ser137Arg (chr4-54013873-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012110.4(CHIC2):c.411C>G(p.Ser137Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,164 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CHIC2
NM_012110.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.75

Variant links:

Genes affected

CHIC2 (HGNC:1935): (cysteine rich hydrophobic domain 2) This gene encodes a member of the CHIC family of proteins. The encoded protein contains a cysteine-rich hydrophobic (CHIC) motif, and is localized to vesicular structures and the plasma membrane. This gene is associated with some cases of acute myeloid leukemia. [provided by RefSeq, Jul 2008]

CHIC2 links:

ENSG00000282278 (HGNC:):

ENSG00000282278 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHIC2	NM_012110.4 link	c.411C>G	p.Ser137Arg	missense_variant	Exon 5 of 6	ENST00000263921.8	NP_036242.1	Q9UKJ5
CHIC2	XM_006714037.5 link	c.327C>G	p.Ser109Arg	missense_variant	Exon 5 of 6		XP_006714100.1
CHIC2	XM_047450063.1 link	c.303C>G	p.Ser101Arg	missense_variant	Exon 6 of 7		XP_047306019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHIC2	ENST00000263921.8 link	c.411C>G	p.Ser137Arg	missense_variant	Exon 5 of 6	1	NM_012110.4	ENSP00000263921.3	Q9UKJ5
ENSG00000282278	ENST00000507166.5 link	c.1018-261052G>C		intron_variant	Intron 12 of 23	2		ENSP00000423325.1	A0A0B4J203
CHIC2	ENST00000512964.5 link	c.354C>G	p.Ser118Arg	missense_variant	Exon 4 of 5	5		ENSP00000425238.1	D6RDW7
CHIC2	ENST00000510894.1 link	c.324C>G	p.Ser108Arg	missense_variant	Exon 5 of 6	2		ENSP00000421032.1	H0Y8H1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250862

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135566

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.411C>G (p.S137R) alteration is located in exon 5 (coding exon 5) of the CHIC2 gene. This alteration results from a C to G substitution at nucleotide position 411, causing the serine (S) at amino acid position 137 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

D;T

M_CAP

Benign

0.0077

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.22

Sift

Benign

0.56

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.71

P;.

Vest4

0.81

MutPred

0.35

Loss of ubiquitination at K140 (P = 0.0402);.;

MVP

0.47

MPC

1.2

ClinPred

0.28

GERP RS

5.6

Varity_R

0.43

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over