2-100968275-C-T

Variant names:

• chr2-100968275-C-T
• rs115806641
• NM_002518.4:c.908-6C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002518.4(NPAS2):​c.908-6C>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00001749
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.609
• Publications: 1 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]

ACMG classification

Our verdict: Benign. The variant received -16 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_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1048 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS2	NM_002518.4	c.908-6C>T		splice_region_variant, intron_variant	Intron 10 of 20	ENST00000335681.10	NP_002509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAS2	ENST00000335681.10	c.908-6C>T		splice_region_variant, intron_variant	Intron 10 of 20	1	NM_002518.4	ENSP00000338283.5
NPAS2	ENST00000448812.5	c.566-6C>T		splice_region_variant, intron_variant	Intron 5 of 6	5		ENSP00000388528.1

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

GnomAD2 exomes AF: 0.00760 AC: 1910 AN: 251170 AF XY: 0.00813

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 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

African (AFR) AF: 0.00167 AC: 56 AN: 33456

American (AMR) AF: 0.00313 AC: 140 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0121 AC: 1047 AN: 86200

European-Finnish (FIN) AF: 0.0115 AC: 616 AN: 53410

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.0106 AC: 11826 AN: 1111346

Other (OTH) AF: 0.00741 AC: 447 AN: 60362

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

African (AFR) AF: 0.00207 AC: 86 AN: 41516

American (AMR) AF: 0.00308 AC: 47 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4814

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 693 AN: 68008

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.55
DANN	Benign	0.76
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115806641; hg19: chr2-101584737;