rs146439095

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2

The NM_013390.3(CEMIP2):c.491A>T(p.Asp164Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,606,754 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 11 hom. )

Consequence

CEMIP2
NM_013390.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.08537677).

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEMIP2	NM_013390.3 linkuse as main transcript	c.491A>T	p.Asp164Val	missense_variant	4/24	ENST00000377044.9	NP_037522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEMIP2	ENST00000377044.9 linkuse as main transcript	c.491A>T	p.Asp164Val	missense_variant	4/24	1	NM_013390.3	ENSP00000366243	P1	Q9UHN6-1
CEMIP2	ENST00000377066.9 linkuse as main transcript	c.491A>T	p.Asp164Val	missense_variant	4/23	1		ENSP00000366266		Q9UHN6-2
CEMIP2	ENST00000542935.5 linkuse as main transcript	c.491A>T	p.Asp164Val	missense_variant, NMD_transcript_variant	4/24	1		ENSP00000437750

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

269

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00990

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00234

AC:

575

AN:

245568

Hom.:

AF XY:

0.00227

AC XY:

303

AN XY:

133198

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000755

Gnomad FIN exome

AF:

0.00722

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00264

AC:

3838

AN:

1454554

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

1829

AN XY:

723326

show subpopulations

Gnomad4 AFR exome

AF:

0.000270

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000813

Gnomad4 FIN exome

AF:

0.00659

Gnomad4 NFE exome

AF:

0.00297

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00177

AC:

269

AN:

152200

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00990

Gnomad4 NFE

AF:

0.00204

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000755

Hom.:

Bravo

AF:

0.00104

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00236

AC:

287

EpiCase

AF:

0.00191

EpiControl

AF:

0.00273

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 25, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Asp164Val var iant in TMEM2 has not been previously associated with disease, but has been iden tified in 0.4% (227/65708) of European chromosomes and 0.6% (39/6602) Finnish ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs146439095). Computational prediction tools and conservation analysi s suggest that the variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, while the clinical s ignificance of the p.Lys132Arg variant is uncertain, its frequency suggests that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.085

T;T

MetaSVM

Pathogenic

0.95

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;P

Vest4

0.96

MVP

0.77

MPC

0.85

ClinPred

0.097

GERP RS

5.9

Varity_R

0.90

gMVP

0.92

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

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