Genetic Variant CEMIP2:p.Ser1340Arg (chr9-71685331-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_013390.3(CEMIP2):c.4018A>C(p.Ser1340Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 1,603,678 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

CEMIP2
NM_013390.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31

Variant links:

Genes affected

CEMIP2 (HGNC:11869): (cell migration inducing hyaluronidase 2) This gene encodes a type II transmembrane protein that belongs to the interferon-induced transmembrane (IFITM) protein superfamily. The encoded protein functions as a cell surface hyaluronidase that cleaves extracellular high molecular weight hyaluronan into intermediate size fragments before internalization and degradation in the lysosome. It also has an interferon-mediated antiviral function in humans through activation of the JAK STAT signaling pathway. The activation of this gene by transcription factor SOX4 in breast cancer cells has been shown to mediate the pathological effects of SOX4 on cancer progression. Naturally occurring mutations in this gene are associated with autosomal recessive non-syndromic hearing loss. [provided by RefSeq, Mar 2017]

CEMIP2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32494467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEMIP2	NM_013390.3 link	c.4018A>C	p.Ser1340Arg	missense_variant	Exon 24 of 24	ENST00000377044.9	NP_037522.1	Q9UHN6-1A0A024R229

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEMIP2	ENST00000377044.9 link	c.4018A>C	p.Ser1340Arg	missense_variant	Exon 24 of 24	1	NM_013390.3	ENSP00000366243.4		Q9UHN6-1

Frequencies

GnomAD3 genomes

AF:

0.0000139

AC:

AN:

143406

Hom.:

Cov.:

show subpopulations

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:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249266

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134806

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000425

AC:

AN:

1460272

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726422

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000549

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000139

AC:

AN:

143406

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

68934

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000298

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

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

May 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4018A>C (p.S1340R) alteration is located in exon 24 (coding exon 23) of the TMEM2 gene. This alteration results from a A to C substitution at nucleotide position 4018, causing the serine (S) at amino acid position 1340 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

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

T;.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.58

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.67

T;T;D

Polyphen

0.80

P;P;.

Vest4

0.49

MutPred

0.71

Loss of ubiquitination at K1336 (P = 0.0342);.;.;

MVP

0.66

MPC

0.20

ClinPred

0.41

GERP RS

5.5

Varity_R

0.25

gMVP

0.78

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

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