2-190514472-C-T

Position:

• chr2-190514472-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142645.2(NEMP2):​c.934G>A​(p.Ala312Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,020 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NEMP2 NM_001142645.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

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=0.06642929).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEMP2	NM_001142645.2	c.934G>A	p.Ala312Thr	missense_variant	7/9	ENST00000409150.8	NP_001136117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEMP2	ENST00000409150.8	c.934G>A	p.Ala312Thr	missense_variant	7/9	2	NM_001142645.2	ENSP00000386292	P1
NEMP2	ENST00000414176.5	c.*195G>A		3_prime_UTR_variant, NMD_transcript_variant	6/7	2		ENSP00000404283
NEMP2	ENST00000444545.5	c.*515G>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	3		ENSP00000403867

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399020 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 690036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000112

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.: 32

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

Mar 29, 2022

The c.934G>A (p.A312T) alteration is located in exon 7 (coding exon 7) of the NEMP2 gene. This alteration results from a G to A substitution at nucleotide position 934, causing the alanine (A) at amino acid position 312 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.10
Sift	Benign	0.46	T
Sift4G	Benign	0.092	T
Polyphen		0.11	B
Vest4		0.080
MutPred		0.56		Gain of phosphorylation at A312 (P = 0.0709);
MVP		0.17
ClinPred		0.11	T
GERP RS		2.6
Varity_R		0.025
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1690480081; hg19: chr2-191379198;