2-100974804-A-G

Variant names:

• chr2-100974804-A-G
• rs1676856288
• NM_002518.4:c.1142A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002518.4(NPAS2):​c.1142A>G​(p.Asp381Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: NPAS2 NM_002518.4 missense, splice_region
• Scores: Splicing: ADA: 0.6982
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

Genes affected

NPAS2 (HGNC:7895): (neuronal PAS domain protein 2) The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors. A similar mouse protein may play a regulatory role in the acquisition of specific types of memory. It also may function as a part of a molecular clock operative in the mammalian forebrain. [provided by RefSeq, Jul 2008]

NPAS2-AS1 (HGNC:40408): (NPAS2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14817119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS2	NM_002518.4	c.1142A>G	p.Asp381Gly	missense_variant, splice_region_variant	Exon 13 of 21	ENST00000335681.10	NP_002509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAS2	ENST00000335681.10	c.1142A>G	p.Asp381Gly	missense_variant, splice_region_variant	Exon 13 of 21	1	NM_002518.4	ENSP00000338283.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1142A>G (p.D381G) alteration is located in exon 13 (coding exon 12) of the NPAS2 gene. This alteration results from a A to G substitution at nucleotide position 1142, causing the aspartic acid (D) at amino acid position 381 to be replaced by a glycine (G). 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	0.074
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.080
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.034
Sift	Uncertain	0.014	D
Sift4G	Benign	0.39	T
Polyphen		0.0060	B
Vest4		0.44
MVP		0.19
MPC		0.43
ClinPred		0.63	D
GERP RS		4.7
Varity_R		0.15
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.70
dbscSNV1_RF	Benign	0.52
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: rs1676856288; hg19: chr2-101591266;