chr2-190517573-C-T

Position:

• chr2-190517573-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001142645.2(NEMP2):​c.559G>A​(p.Val187Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NEMP2 NM_001142645.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.796

Genes affected

NEMP2 (HGNC:33700): (nuclear envelope integral membrane protein 2) Predicted to be located in nuclear inner membrane. Predicted to be integral component of membrane. Predicted to be active in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07744482).
• BP6: Variant 2-190517573-C-T is Benign according to our data. Variant chr2-190517573-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3193526.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEMP2	NM_001142645.2	c.559G>A	p.Val187Ile	missense_variant	5/9	ENST00000409150.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEMP2	ENST00000409150.8	c.559G>A	p.Val187Ile	missense_variant	5/9	2	NM_001142645.2	P1
NEMP2	ENST00000414176.5	c.352G>A	p.Val118Ile	missense_variant, NMD_transcript_variant	5/7	2
NEMP2	ENST00000343105.9	c.*140G>A		3_prime_UTR_variant, NMD_transcript_variant	5/6	4
NEMP2	ENST00000444545.5	c.*140G>A		3_prime_UTR_variant, NMD_transcript_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398252 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 689676

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.2
DANN	Benign	0.53
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.070
Sift	Benign	1.0	T
Sift4G	Benign	0.50	T
Polyphen		0.19	B
Vest4		0.082
MutPred		0.58		Gain of helix (P = 0.1736);
MVP		0.11
ClinPred		0.056	T
GERP RS		-5.4
Varity_R		0.014
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1690605570; hg19: chr2-191382299;