Genetic Variant NM_014268.4:c.427C>T (chr18-35101976-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_014268.4(MAPRE2):c.427C>T(p.Arg143Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAPRE2
NM_014268.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.16

Publications

4 publications found

Variant links:

Genes affected

MAPRE2 (HGNC:6891): (microtubule associated protein RP/EB family member 2) The protein encoded by this gene shares significant homology to the adenomatous polyposis coli (APC) protein-binding EB1 gene family. This protein is a microtubule-associated protein that is necessary for spindle symmetry during mitosis. It is thought to play a role in the tumorigenesis of colorectal cancers and the proliferative control of normal cells. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2012]

MAPRE2 Gene-Disease associations (from GenCC):

skin creases, congenital symmetric circumferential, 2
Inheritance: Unknown, AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
multiple benign circumferential skin creases on limbs
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MAPRE2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-35101976-C-T is Pathogenic according to our data. Variant chr18-35101976-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 218930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014268.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPRE2	NM_014268.4	MANE Select	c.427C>T	p.Arg143Cys	missense	Exon 4 of 7	NP_055083.1	Q15555-1
MAPRE2	NM_001143827.3		c.391C>T	p.Arg131Cys	missense	Exon 5 of 8	NP_001137299.1	Q15555-3
MAPRE2	NM_001143826.3		c.298C>T	p.Arg100Cys	missense	Exon 5 of 8	NP_001137298.1	Q15555-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPRE2	ENST00000300249.10	TSL:1 MANE Select	c.427C>T	p.Arg143Cys	missense	Exon 4 of 7	ENSP00000300249.4	Q15555-1
MAPRE2	ENST00000588910.5	TSL:1	c.427C>T	p.Arg143Cys	missense	Exon 4 of 5	ENSP00000468588.1	Q15555-2
MAPRE2	ENST00000942657.1		c.424C>T	p.Arg142Cys	missense	Exon 4 of 7	ENSP00000612716.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1456792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724640

African (AFR)

AF:

0.00

AC:

AN:

33172

American (AMR)

AF:

0.00

AC:

AN:

44010

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.00

AC:

AN:

39416

South Asian (SAS)

AF:

0.00

AC:

AN:

85428

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109812

Other (OTH)

AF:

0.00

AC:

AN:

60152

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Skin creases, congenital symmetric circumferential, 2 (2)

Developmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.8

PhyloP100

3.2

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.35

Sift

Benign

0.043

Sift4G

Uncertain

0.031

Polyphen

0.15

Vest4

0.75

MutPred

0.62

Loss of MoRF binding (P = 0.065)

MVP

0.78

MPC

2.2

ClinPred

0.98

GERP RS

5.3

Varity_R

0.78

gMVP

0.90

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over