11-95979394-A-C

Position:

chr11-95979394-A-C

Variant summary

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

The NM_032427.4(MAML2):c.3025T>G(p.Phe1009Val) variant causes a missense change. The variant allele was found at a frequency of 0.000456 in 1,613,562 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 1 hom. )

Consequence

MAML2
NM_032427.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.70

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=0.05877301).

BS2

High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAML2	NM_032427.4 linkuse as main transcript	c.3025T>G	p.Phe1009Val	missense_variant	5/5	ENST00000524717.6	NP_115803.1	Q8IZL2
MAML2	XM_011543023.4 linkuse as main transcript	c.2584T>G	p.Phe862Val	missense_variant	5/5		XP_011541325.1
MAML2	XM_047427710.1 linkuse as main transcript	c.2341T>G	p.Phe781Val	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.3025T>G	p.Phe1009Val	missense_variant	5/5	1	NM_032427.4	ENSP00000434552.1		Q8IZL2

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000588

AC:

146

AN:

248148

Hom.:

AF XY:

0.000542

AC XY:

AN XY:

134638

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00191

Gnomad NFE exome

AF:

0.000889

Gnomad OTH exome

AF:

0.000830

GnomAD4 exome

AF:

0.000446

AC:

652

AN:

1461356

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

362

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00210

Gnomad4 NFE exome

AF:

0.000465

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000552

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.000956

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000677

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000960

AC:

ExAC

AF:

0.000562

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000535

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MAML2 p.Phe1009Val variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs182630516) and in control databases in 184 of 279532 chromosomes at a frequency of 0.000658 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 47 of 24982 chromosomes (freq: 0.001881), European (non-Finnish) in 131 of 127894 chromosomes (freq: 0.001024) and Other in 6 of 7112 chromosomes (freq: 0.000844), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian or South Asian populations. The p.Phe1009 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing at the variant location. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

D;D

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.4

D;.

REVEL

Uncertain

0.52

Sift

Uncertain

0.0020

D;.

Sift4G

Benign

0.50

T;T

Polyphen

1.0

D;.

Vest4

0.74

MVP

0.60

MPC

0.078

ClinPred

0.22

GERP RS

5.5

Varity_R

0.78

gMVP

0.59

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