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GeneBe

2-100974889-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_002518.4(NPAS2):c.1227G>A(p.Ser409=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,016 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0064 ( 14 hom., cov: 33)
Exomes 𝑓: 0.00073 ( 10 hom. )

Consequence

NPAS2
NM_002518.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.03
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-100974889-G-A is Benign according to our data. Variant chr2-100974889-G-A is described in ClinVar as [Benign]. Clinvar id is 773841.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-4.03 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00643 (979/152246) while in subpopulation AFR AF= 0.0224 (932/41534). AF 95% confidence interval is 0.0212. There are 14 homozygotes in gnomad4. There are 464 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 979 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPAS2NM_002518.4 linkuse as main transcriptc.1227G>A p.Ser409= synonymous_variant 13/21 ENST00000335681.10
NPAS2-AS1NR_110213.1 linkuse as main transcriptn.575+396C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPAS2ENST00000335681.10 linkuse as main transcriptc.1227G>A p.Ser409= synonymous_variant 13/211 NM_002518.4 P1
NPAS2-AS1ENST00000652285.1 linkuse as main transcriptn.605+396C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00644
AC:
979
AN:
152128
Hom.:
14
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0225
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00223
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00185
AC:
466
AN:
251386
Hom.:
12
AF XY:
0.00133
AC XY:
181
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.0250
Gnomad AMR exome
AF:
0.000983
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000728
AC:
1064
AN:
1461770
Hom.:
10
Cov.:
35
AF XY:
0.000633
AC XY:
460
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.0237
Gnomad4 AMR exome
AF:
0.00110
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000120
Gnomad4 OTH exome
AF:
0.00119
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00643
AC:
979
AN:
152246
Hom.:
14
Cov.:
33
AF XY:
0.00623
AC XY:
464
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.0224
Gnomad4 AMR
AF:
0.00222
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00321
Hom.:
1
Bravo
AF:
0.00725
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.000296

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 31, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
Cadd
Benign
0.059
Dann
Benign
0.91

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: rs116479799; hg19: chr2-101591351; API