2-100975538-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

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. 14/21 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

Scores

2
17

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.77
Variant links:
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)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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 id 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPAS2NM_002518.4 linkuse as main transcriptc.1363C>G p.Pro455Ala missense_variant 14/21 ENST00000335681.10
NPAS2-AS1NR_110213.1 linkuse as main transcriptn.447-125G>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPAS2ENST00000335681.10 linkuse as main transcriptc.1363C>G p.Pro455Ala missense_variant 14/211 NM_002518.4 P1
NPAS2-AS1ENST00000652285.1 linkuse as main transcriptn.471G>C non_coding_transcript_exon_variant 2/6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Non-obstructive azoospermia Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchLupski Lab, Baylor-Hopkins CMG, Baylor College of MedicineAug 01, 2015- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.083
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.0
L;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.54
N;N
REVEL
Benign
0.047
Sift
Benign
0.98
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0040
B;.
Vest4
0.68
MVP
0.20
MPC
0.33
ClinPred
0.47
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.023
gMVP
0.23

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs879253743; hg19: chr2-101592000; API