chr2-100977729-C-T

Position:

• chr2-100977729-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002518.4(NPAS2):​c.1412C>T​(p.Ser471Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,613,442 control chromosomes in the GnomAD database, including 22,385 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1555 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20830 hom.)
• Consequence: NPAS2 NM_002518.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014803708).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPAS2	NM_002518.4	c.1412C>T	p.Ser471Leu	missense_variant	15/21	ENST00000335681.10	NP_002509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPAS2	ENST00000335681.10	c.1412C>T	p.Ser471Leu	missense_variant	15/21	1	NM_002518.4	ENSP00000338283.5

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20721 AN: 152120 Hom.: 1555 Cov.: 32

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0971

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.136 AC: 34140 AN: 251350 Hom.: 2754 AF XY: 0.140 AC XY: 18993 AN XY: 135862

Gnomad AFR exome AF: 0.0822

Gnomad AMR exome AF: 0.0900

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.162 AC: 236869 AN: 1461204 Hom.: 20830 Cov.: 32 AF XY: 0.161 AC XY: 116891 AN XY: 726920

Gnomad4 AFR exome AF: 0.0831

Gnomad4 AMR exome AF: 0.0953

Gnomad4 ASJ exome AF: 0.162

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.136 AC: 20719 AN: 152238 Hom.: 1555 Cov.: 32 AF XY: 0.136 AC XY: 10129 AN XY: 74426

Gnomad4 AFR AF: 0.0839

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0972

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.149

Alfa AF: 0.162 Hom.: 3268

Bravo AF: 0.132

TwinsUK AF: 0.179 AC: 664

ALSPAC AF: 0.173 AC: 667

ESP6500AA AF: 0.0867 AC: 382

ESP6500EA AF: 0.182 AC: 1565

ExAC AF: 0.136 AC: 16556

Asia WGS AF: 0.0420 AC: 151 AN: 3478

EpiCase AF: 0.176

EpiControl AF: 0.180

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.12
Sift	Benign	0.38	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0070	B;.
Vest4		0.061
MPC		0.25
ClinPred		0.016	T
GERP RS		5.7
Varity_R		0.045
gMVP		0.30

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: rs11541353; hg19: chr2-101594191; COSMIC: COSV59560524; COSMIC: COSV59560524;