11-95979921-G-A

Position:

• chr11-95979921-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032427.4(MAML2):​c.2498C>T​(p.Ala833Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAML2 NM_032427.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.117528826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAML2	NM_032427.4	c.2498C>T	p.Ala833Val	missense_variant	5/5	ENST00000524717.6	NP_115803.1
MAML2	XM_011543023.4	c.2057C>T	p.Ala686Val	missense_variant	5/5		XP_011541325.1
MAML2	XM_047427710.1	c.1814C>T	p.Ala605Val	missense_variant	5/5		XP_047283666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAML2	ENST00000524717.6	c.2498C>T	p.Ala833Val	missense_variant	5/5	1	NM_032427.4	ENSP00000434552.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

The c.2498C>T (p.A833V) alteration is located in exon 5 (coding exon 5) of the MAML2 gene. This alteration results from a C to T substitution at nucleotide position 2498, causing the alanine (A) at amino acid position 833 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.016
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.083
Sift	Benign	0.74	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.099	B;.
Vest4		0.068
MutPred		0.087		Loss of glycosylation at S837 (P = 0.1841);.;
MVP		0.15
MPC		0.061
ClinPred		0.63	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-95713085;