Genetic Variant CEMIP:p.Leu83Leu (chr15-80879723-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001293298.2(CEMIP):c.249G>A(p.Leu83Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,614,116 control chromosomes in the GnomAD database, including 1,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 1042 hom., cov: 33)

Exomes 𝑓: 0.0083 ( 924 hom. )

Consequence

CEMIP
NM_001293298.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.25

Publications

2 publications found

Variant links:

Genes affected

CEMIP (HGNC:29213): (cell migration inducing hyaluronidase 1) Enables several functions, including clathrin heavy chain binding activity; hyaluronic acid binding activity; and hyalurononglucosaminidase activity. Involved in several processes, including hyaluronan catabolic process; positive regulation of protein phosphorylation; and positive regulation of transport. Located in clathrin-coated endocytic vesicle; endoplasmic reticulum; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CEMIP Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

CEMIP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 15-80879723-G-A is Benign according to our data. Variant chr15-80879723-G-A is described in ClinVar as Benign. ClinVar VariationId is 585660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001293298.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEMIP	NM_001293298.2	MANE Select	c.249G>A	p.Leu83Leu	synonymous	Exon 5 of 30	NP_001280227.1
CEMIP	NM_001293304.2		c.249G>A	p.Leu83Leu	synonymous	Exon 5 of 30	NP_001280233.1
CEMIP	NM_018689.3		c.249G>A	p.Leu83Leu	synonymous	Exon 4 of 29	NP_061159.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEMIP	ENST00000394685.8	TSL:1 MANE Select	c.249G>A	p.Leu83Leu	synonymous	Exon 5 of 30	ENSP00000378177.3
CEMIP	ENST00000220244.7	TSL:1	c.249G>A	p.Leu83Leu	synonymous	Exon 4 of 29	ENSP00000220244.3
CEMIP	ENST00000356249.9	TSL:1	c.249G>A	p.Leu83Leu	synonymous	Exon 5 of 30	ENSP00000348583.5

Frequencies

GnomAD3 genomes

AF:

0.0638

AC:

9702

AN:

152136

Hom.:

1033

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0287

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00272

Gnomad OTH

AF:

0.0469

GnomAD2 exomes

AF:

0.0185

AC:

4644

AN:

251230

AF XY:

0.0138

show subpopulations

Gnomad AFR exome

AF:

0.225

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00263

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00831

AC:

12155

AN:

1461862

Hom.:

924

Cov.:

AF XY:

0.00734

AC XY:

5336

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.225

AC:

7518

AN:

33474

American (AMR)

AF:

0.0168

AC:

752

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00754

AC:

197

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.000533

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0225

AC:

130

AN:

5768

European-Non Finnish (NFE)

AF:

0.00219

AC:

2433

AN:

1111994

Other (OTH)

AF:

0.0177

AC:

1071

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

630

1261

1891

2522

3152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0640

AC:

9742

AN:

152254

Hom.:

1042

Cov.:

AF XY:

0.0623

AC XY:

4641

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.216

AC:

8975

AN:

41516

American (AMR)

AF:

0.0285

AC:

436

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00272

AC:

185

AN:

68028

Other (OTH)

AF:

0.0483

AC:

102

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

389

778

1166

1555

1944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0303

Hom.:

283

Bravo

AF:

0.0727

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00284

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

CEMIP-related disorder

Benign:1

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.038

(source)

DANN

Benign

0.52

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over