Genetic Variant NM_001039958.2:c.197C>A (chr15-89776554-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039958.2(MESP2):c.197C>A(p.Ala66Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,379,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A66T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

MESP2
NM_001039958.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.23

Publications

4 publications found

Variant links:

Genes affected

MESP2 (HGNC:29659): (mesoderm posterior bHLH transcription factor 2) This gene encodes a member of the bHLH family of transcription factors and plays a key role in defining the rostrocaudal patterning of somites via interactions with multiple Notch signaling pathways. This gene is expressed in the anterior presomitic mesoderm and is downregulated immediately after the formation of segmented somites. This gene also plays a role in the formation of epithelial somitic mesoderm and cardiac mesoderm. Mutations in the MESP2 gene cause autosomal recessive spondylocostal dystosis 2 (SCD02). [provided by RefSeq, Oct 2008]

MESP2 Gene-Disease associations (from GenCC):

spondylocostal dysostosis 2, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive spondylocostal dysostosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MESP2 links:

LOC124903550 (HGNC:):

LOC124903550 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1222316).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039958.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP2	NM_001039958.2	MANE Select	c.197C>A	p.Ala66Glu	missense	Exon 1 of 2	NP_001035047.1	Q0VG99

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MESP2	ENST00000341735.5	TSL:1 MANE Select	c.197C>A	p.Ala66Glu	missense	Exon 1 of 2	ENSP00000342392.3	Q0VG99
MESP2	ENST00000560219.2	TSL:1	c.31-1511C>A		intron	N/A	ENSP00000452998.1	H0YKZ5
MESP2	ENST00000558723.1	TSL:3	n.39-1511C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1379838

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

680780

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30648

American (AMR)

AF:

0.00

AC:

AN:

35532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24956

East Asian (EAS)

AF:

0.00

AC:

AN:

35192

South Asian (SAS)

AF:

0.00

AC:

AN:

78690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5170

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

1077048

Other (OTH)

AF:

0.00

AC:

AN:

57614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.13

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.39

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

PhyloP100

3.2

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.79

REVEL

Benign

0.065

Sift

Benign

0.058

Sift4G

Benign

0.071

Polyphen

0.060

Vest4

0.31

MutPred

0.34

Loss of MoRF binding (P = 0.0494)

MVP

0.43

MPC

1.1

ClinPred

0.38

GERP RS

0.21

PromoterAI

0.23

Neutral

(source)

Varity_R

0.15

gMVP

0.30

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over