Variant 11-95979556-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032427.4(MAML2):c.2863G>A(p.Val955Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,613,720 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 1 hom. )

Consequence

MAML2
NM_032427.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.15

Variant links:

Genes affected

MAML2 (HGNC:16259): (mastermind like transcriptional coactivator 2) The protein encoded by this gene is a member of the Mastermind-like family of proteins. All family members are proline and glutamine-rich, and contain a conserved basic domain that binds the ankyrin repeat domain of the intracellular domain of the Notch receptors (ICN1-4) in their N-terminus, and a transcriptional activation domain in their C-terminus. This protein binds to an extended groove that is formed by the interaction of CBF1, Suppressor of Hairless, LAG-1 (CSL) with ICN, and positively regulates Notch signaling. High levels of expression of this gene have been observed in several B cell-derived lymphomas. Translocations resulting in fusion proteins with both CRTC1 and CRTC3 have been implicated in the development of mucoepidermoid carcinomas, while a translocation event with CXCR4 has been linked with chronic lymphocytic leukemia (CLL). Copy number variation in the polyglutamine tract has been observed. [provided by RefSeq, Jan 2015]

MAML2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01904288).

BS2

High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAML2	NM_032427.4 linkuse as main transcript	c.2863G>A	p.Val955Ile	missense_variant	5/5	ENST00000524717.6	NP_115803.1	Q8IZL2
MAML2	XM_011543023.4 linkuse as main transcript	c.2422G>A	p.Val808Ile	missense_variant	5/5		XP_011541325.1
MAML2	XM_047427710.1 linkuse as main transcript	c.2179G>A	p.Val727Ile	missense_variant	5/5		XP_047283666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAML2	ENST00000524717.6 linkuse as main transcript	c.2863G>A	p.Val955Ile	missense_variant	5/5	1	NM_032427.4	ENSP00000434552.1		Q8IZL2

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000723

AC:

AN:

248844

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

134996

show subpopulations

Gnomad AFR exome

AF:

0.000969

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461650

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000408

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00133

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000184

Hom.:

Bravo

AF:

0.000393

ESP6500AA

AF:

0.00121

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000992

AC:

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

Ambry Genetics

Feb 02, 2024

The c.2863G>A (p.V955I) alteration is located in exon 5 (coding exon 5) of the MAML2 gene. This alteration results from a G to A substitution at nucleotide position 2863, causing the valine (V) at amino acid position 955 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0053

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.0

L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.35

N;.

REVEL

Benign

0.12

Sift

Benign

0.41

T;.

Sift4G

Benign

0.36

T;T

Polyphen

1.0

D;.

Vest4

0.051

MVP

0.49

MPC

0.052

ClinPred

0.044

GERP RS

5.3

Varity_R

0.066

gMVP

0.31

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

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