18-35101976-C-T

Position:

• chr18-35101976-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The ENST00000300249.10(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 ENST00000300249.10 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.16

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a domain Calponin-homology (CH) (size 102) in uniprot entity MARE2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in ENST00000300249.10
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAPRE2. . Gene score misZ 3.1867 (greater than the threshold 3.09). Trascript score misZ 4.3282 (greater than threshold 3.09). GenCC has associacion of gene with multiple benign circumferential skin creases on limbs 1, skin creases, congenital symmetric circumferential, 2, multiple benign circumferential skin creases on limbs.
• PP5: Variant 18-35101976-C-T is Pathogenic according to our data. Variant chr18-35101976-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-35101976-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPRE2	NM_014268.4	c.427C>T	p.Arg143Cys	missense_variant	4/7	ENST00000300249.10	NP_055083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPRE2	ENST00000300249.10	c.427C>T	p.Arg143Cys	missense_variant	4/7	1	NM_014268.4	ENSP00000300249	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1456792 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724640

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Skin creases, congenital symmetric circumferential, 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 03, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MAPRE2-related disorder (ClinVar ID: VCV000218930 / PMID: 26637975). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26637975). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Developmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Sep 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;T;.;D;D;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	.;.;.;.;.;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.4	.;D;.;D;.;D;D;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.043	.;D;.;D;.;T;D;.;.
Sift4G	Uncertain	0.031	D;D;D;T;D;T;D;T;D
Polyphen		0.15, 0.093	.;.;.;.;.;B;.;B;.
Vest4		0.75, 0.81, 0.80, 0.77, 0.81, 0.85
MutPred		0.62		.;.;.;.;.;Loss of MoRF binding (P = 0.065);.;Loss of MoRF binding (P = 0.065);.;
MVP		0.78
MPC		2.2
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.78
gMVP		0.90

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

Other links and lift over

dbSNP: rs864309720; hg19: chr18-32681940;