19-308586-T-C

Position:

• chr19-308586-T-C

Variant summary

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

The NM_017550.3(MIER2):​c.1189A>G​(p.Met397Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MIER2 NM_017550.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.454

Genes affected

MIER2 (HGNC:29210): (MIER family member 2) Enables histone deacetylase binding activity. Contributes to histone deacetylase activity. Involved in histone deacetylation. Located in cytoplasm and nucleus. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

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
MIER2	NM_017550.3	c.1189A>G	p.Met397Val	missense_variant	12/14	ENST00000264819.7	NP_060020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIER2	ENST00000264819.7	c.1189A>G	p.Met397Val	missense_variant	12/14	1	NM_017550.3	ENSP00000264819.3
MIER2	ENST00000619835.4	c.181A>G	p.Met61Val	missense_variant	2/4	3		ENSP00000482489.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451530 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721336

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: 0.00

GnomAD4 genome Cov.: 33

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 17, 2024

The c.1189A>G (p.M397V) alteration is located in exon 12 (coding exon 12) of the MIER2 gene. This alteration results from a A to G substitution at nucleotide position 1189, causing the methionine (M) at amino acid position 397 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	0.072
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.40
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.0080
Sift	Benign	0.45	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.087
MutPred		0.10		Gain of phosphorylation at T399 (P = 0.098);
MVP		0.068
MPC		0.20
ClinPred		0.071	T
GERP RS		-1.9
Varity_R		0.025
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1970773713; hg19: chr19-308586;