rs146893880

Variant names:

• chr2-100974878-C-G
• rs146893880
• NM_002518.4:c.1216C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-100974878-C-G
• chr2-100974878-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002518.4(NPAS2):​c.1216C>G​(p.His406Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,084 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (10 hom.)
• Consequence: NPAS2 NM_002518.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.51
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030507743).
• BP6: Variant 2-100974878-C-G is Benign according to our data. Variant chr2-100974878-C-G is described in ClinVar as Benign. ClinVar VariationId is 788958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00598 (911/152300) while in subpopulation AFR AF = 0.0206 (858/41572). AF 95% confidence interval is 0.0195. There are 8 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 911 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002518.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS2	NM_002518.4	MANE Select	c.1216C>G	p.His406Asp	missense	Exon 13 of 21	NP_002509.2
	NPAS2-AS1	NR_110213.1		n.575+407G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS2	ENST00000335681.10	TSL:1 MANE Select	c.1216C>G	p.His406Asp	missense	Exon 13 of 21	ENSP00000338283.5	Q99743
	NPAS2	ENST00000474550.5	TSL:1	n.550C>G		non_coding_transcript_exon	Exon 2 of 9
	NPAS2	ENST00000906777.1		c.1216C>G	p.His406Asp	missense	Exon 14 of 22	ENSP00000576836.1

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 911 AN: 152182 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.000235

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00160 AC: 403 AN: 251410 AF XY: 0.00124

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000740 AC: 1081 AN: 1461784 Hom.: 10 Cov.: 35 AF XY: 0.000663 AC XY: 482 AN XY: 727200

African (AFR) AF: 0.0220 AC: 735 AN: 33468

American (AMR) AF: 0.00121 AC: 54 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1111942

Other (OTH) AF: 0.00131 AC: 79 AN: 60384

GnomAD4 genome AF: 0.00598 AC: 911 AN: 152300 Hom.: 8 Cov.: 33 AF XY: 0.00584 AC XY: 435 AN XY: 74458

African (AFR) AF: 0.0206 AC: 858 AN: 41572

American (AMR) AF: 0.00209 AC: 32 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00115 Hom.: 1

Bravo AF: 0.00699

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00195 AC: 237

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.091
Sift	Benign	0.71	T
Sift4G	Benign	0.49	T
Polyphen		0.019	B
Vest4		0.25
MVP		0.20
MPC		0.40
ClinPred		0.018	T
GERP RS		6.2
PromoterAI		-0.0084	Neutral
Varity_R		0.037
gMVP		0.52
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs146893880; hg19: chr2-101591340;