11-95985591-G-A

Position:

• chr11-95985591-G-A

Variant summary

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

The NM_032427.4(MAML2):​c.2395C>T​(p.Pro799Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAML2 NM_032427.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.44

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAML2	NM_032427.4	c.2395C>T	p.Pro799Ser	missense_variant	4/5	ENST00000524717.6	NP_115803.1
MAML2	XM_011543023.4	c.1954C>T	p.Pro652Ser	missense_variant	4/5		XP_011541325.1
MAML2	XM_047427710.1	c.1711C>T	p.Pro571Ser	missense_variant	4/5		XP_047283666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAML2	ENST00000524717.6	c.2395C>T	p.Pro799Ser	missense_variant	4/5	1	NM_032427.4	ENSP00000434552.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460634 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726580

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: 0.0000166

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

Nov 27, 2023

The c.2395C>T (p.P799S) alteration is located in exon 4 (coding exon 4) of the MAML2 gene. This alteration results from a C to T substitution at nucleotide position 2395, causing the proline (P) at amino acid position 799 to be replaced by a serine (S). 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	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0060	D;.
Sift4G	Benign	0.42	T;T
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.17		Gain of phosphorylation at P799 (P = 0.018);.;
MVP		0.39
MPC		0.062
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.37
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-95718755;