rs146439095

chr9-71745561-T-Achr9-71745561-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP3 BP4_Moderate

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.08537677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEMIP2	NM_013390.3	c.491A>T	p.Asp164Val	missense_variant	4/24	ENST00000377044.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEMIP2	ENST00000377044.9	c.491A>T	p.Asp164Val	missense_variant	4/24	1	NM_013390.3	P1
CEMIP2	ENST00000377066.9	c.491A>T	p.Asp164Val	missense_variant	4/23	1
CEMIP2	ENST00000542935.5	c.491A>T	p.Asp164Val	missense_variant, NMD_transcript_variant	4/24	1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152082 Hom.: 1 Cov.: 32

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.: 1 AF XY: 0.00227 AC XY: 303 AN XY: 133198

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.: 11 Cov.: 32 AF XY: 0.00253 AC XY: 1829 AN XY: 723326

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.: 1 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74422

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.: 0

Bravo AF: 0.00104

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

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

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	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.085	T;T
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs146439095; hg19: chr9-74360477;