2-100968275-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002518.4(NPAS2):c.908-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,613,198 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0069 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (90 hom.)
• Consequence: NPAS2 NM_002518.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001749
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.609

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-100968275-C-T is Benign according to our data. Variant chr2-100968275-C-T is described in ClinVar as [Benign]. Clinvar id is 773124.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1049 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPAS2	NM_002518.4	c.908-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000335681.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPAS2	ENST00000335681.10	c.908-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002518.4	P1
NPAS2	ENST00000448812.5	c.567-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00690 AC: 1049 AN: 152052 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00760 AC: 1910 AN: 251170 Hom.: 10 AF XY: 0.00813 AC XY: 1104 AN XY: 135724

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00316

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00982

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00973 AC: 14218 AN: 1461028 Hom.: 90 Cov.: 31 AF XY: 0.00978 AC XY: 7106 AN XY: 726822

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00741

GnomAD4 genome AF: 0.00689 AC: 1048 AN: 152170 Hom.: 4 Cov.: 32 AF XY: 0.00669 AC XY: 498 AN XY: 74392

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00853 Hom.: 3

Bravo AF: 0.00615

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00906

EpiControl AF: 0.00978

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.55
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs115806641; hg19: chr2-101584737;