15-36892360-G-C

Position:

• chr15-36892360-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_170675.5(MEIS2):​c.1247C>G​(p.Pro416Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MEIS2 NM_170675.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEIS2. . Gene score misZ: 2.4571 (greater than the threshold 3.09). Trascript score misZ: 3.4197 (greater than threshold 3.09). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. GenCC has associacion of the gene with syndromic intellectual disability, cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24509352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEIS2	NM_170675.5	c.1247C>G	p.Pro416Arg	missense_variant	12/12	ENST00000561208.6	NP_733775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEIS2	ENST00000561208.6	c.1247C>G	p.Pro416Arg	missense_variant	12/12	1	NM_170675.5	ENSP00000453793.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461718 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727166

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.1247C>G (p.P416R) alteration is located in exon 12 (coding exon 12) of the MEIS2 gene. This alteration results from a C to G substitution at nucleotide position 1247, causing the proline (P) at amino acid position 416 to be replaced by an arginine (R). 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	0.17
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.21	B;B
Vest4		0.46
MutPred		0.33		Gain of catalytic residue at P416 (P = 0.0125);.;
MVP		0.49
MPC		0.0073
ClinPred		0.51	D
GERP RS		5.9
Varity_R		0.18
gMVP		0.62

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

Other links and lift over

dbSNP: rs2055911683; hg19: chr15-37184561;