15-37093609-G-C

Variant names:

• chr15-37093609-G-C
• rs749346955
• NM_170675.5:c.611C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_170675.5(MEIS2):​c.611C>G​(p.Ser204*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEIS2 NM_170675.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0
• Publications: 2 publications found

Genes affected

MEIS2 (HGNC:7001): (Meis homeobox 2) This gene encodes a homeobox protein belonging to the TALE ('three amino acid loop extension') family of homeodomain-containing proteins. TALE homeobox proteins are highly conserved transcription regulators, and several members have been shown to be essential contributors to developmental programs. Multiple transcript variants encoding distinct isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

MEIS2 Gene-Disease associations (from GenCC):

• cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, Illumina
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-37093609-G-C is Pathogenic according to our data. Variant chr15-37093609-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 427215.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170675.5. 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
	MEIS2	NM_170675.5	MANE Select	c.611C>G	p.Ser204*	stop_gained	Exon 6 of 12	NP_733775.1
	MEIS2	NM_001220482.2		c.611C>G	p.Ser204*	stop_gained	Exon 7 of 13	NP_001207411.1
	MEIS2	NM_170676.5		c.611C>G	p.Ser204*	stop_gained	Exon 6 of 12	NP_733776.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEIS2	ENST00000561208.6	TSL:1 MANE Select	c.611C>G	p.Ser204*	stop_gained	Exon 6 of 12	ENSP00000453793.1
	MEIS2	ENST00000338564.9	TSL:1	c.611C>G	p.Ser204*	stop_gained	Exon 7 of 13	ENSP00000341400.4
	MEIS2	ENST00000424352.6	TSL:1	c.611C>G	p.Ser204*	stop_gained	Exon 6 of 13	ENSP00000404185.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.87
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs749346955; hg19: chr15-37385810;