rs879253743

Variant names:

• chr2-100975538-C-G
• rs879253743
• NM_002518.4:c.1363C>G
• NPAS2 p.Pro455Ala

Your query was ambiguous. Multiple possible variants found:

• chr2-100975538-C-G
• chr2-100975538-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_002518.4(NPAS2):​c.1363C>G​(p.Pro455Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPAS2 NM_002518.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.77
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-100975538-C-G is Pathogenic according to our data. Variant chr2-100975538-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 242856.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08313167). . Strength limited to SUPPORTING due to the PP5.

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.1363C>G	p.Pro455Ala	missense	Exon 14 of 21	NP_002509.2
	NPAS2-AS1	NR_110213.1		n.447-125G>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.1363C>G	p.Pro455Ala	missense	Exon 14 of 21	ENSP00000338283.5	Q99743
	NPAS2	ENST00000474550.5	TSL:1	n.697C>G		non_coding_transcript_exon	Exon 3 of 9
	NPAS2	ENST00000906777.1		c.1363C>G	p.Pro455Ala	missense	Exon 15 of 22	ENSP00000576836.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Non-obstructive azoospermia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.047
Sift	Benign	0.98	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.23
Mutation Taster		=14/86	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs879253743;

hg19: chr2-101592000;