Variant chr12-102958393-C-CGCAGCA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_004316.4(ASCL1):c.181_186dup(p.Gln61_Gln62dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 50 hom., cov: 0)

Exomes 𝑓: 0.012 ( 11 hom. )

Consequence

ASCL1
NM_004316.4 inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.219

Variant links:

Genes affected

ASCL1 (HGNC:738): (achaete-scute family bHLH transcription factor 1) This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. Mutations in this gene may contribute to the congenital central hypoventilation syndrome (CCHS) phenotype in rare cases. [provided by RefSeq, Jul 2008]

ASCL1 links:

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 12-102958393-C-CGCAGCA is Benign according to our data. Variant chr12-102958393-C-CGCAGCA is described in ClinVar as [Likely_benign]. Clinvar id is 179579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0211 (3170/150202) while in subpopulation AFR AF= 0.0501 (2054/40988). AF 95% confidence interval is 0.0483. There are 50 homozygotes in gnomad4. There are 1489 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3170 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4 linkuse as main transcript	c.181_186dup	p.Gln61_Gln62dup	inframe_insertion	1/2	ENST00000266744.4
PAH	NM_001354304.2 linkuse as main transcript	c.-295_-294insTGCTGC		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ASCL1	ENST00000266744.4 linkuse as main transcript	c.181_186dup	p.Gln61_Gln62dup	inframe_insertion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1 linkuse as main transcript	n.17_18insTGCTGC		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0211

AC:

3161

AN:

150112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0500

Gnomad AMI

AF:

0.00443

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.00550

Gnomad EAS

AF:

0.00256

Gnomad SAS

AF:

0.00902

Gnomad FIN

AF:

0.00315

Gnomad MID

AF:

0.0321

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0185

GnomAD4 exome

AF:

0.0118

AC:

15996

AN:

1355634

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

7823

AN XY:

668578

show subpopulations

Gnomad4 AFR exome

AF:

0.0485

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.00387

Gnomad4 EAS exome

AF:

0.00730

Gnomad4 SAS exome

AF:

0.00993

Gnomad4 FIN exome

AF:

0.00250

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.0130

GnomAD4 genome

AF:

0.0211

AC:

3170

AN:

150202

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1489

AN XY:

73322

show subpopulations

Gnomad4 AFR

AF:

0.0501

Gnomad4 AMR

AF:

0.0139

Gnomad4 ASJ

AF:

0.00550

Gnomad4 EAS

AF:

0.00257

Gnomad4 SAS

AF:

0.00903

Gnomad4 FIN

AF:

0.00315

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.0183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 25, 2014	Gln51[14] in exon 1 of ASCL1: This variant is not expected to have clinical sign ificance because it has been identified in 1.6% (5/304) of Caucasian control chr omosomes tested by our laboratory. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over