Variant 12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_004316.4(ASCL1):c.163_186delCAGCAGCAGCAGCAGCAGCAGCAG(p.Gln55_Gln62del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,507,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

ASCL1
NM_004316.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.809

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP6

Variant 12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 597419.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.163_186delCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln55_Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-318_-295delTGCTGCTGCTGCTGCTGCTGCTGC		5_prime_UTR_variant	Exon 1 of 14		NP_001341233.1
PAH		n.102958417_102958394delTGCTGCTGCTGCTGCTGCTGCTGC		bidirectional_gene_fusion

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ASCL1	ENST00000266744.4 link	c.163_186delCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln55_Gln62del	conservative_inframe_deletion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.-7_17delTGCTGCTGCTGCTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-318_-295delTGCTGCTGCTGCTGCTGCTGCTGC		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0
PAH	ENST00000547319.1 link	n.-7_17delTGCTGCTGCTGCTGCTGCTGCTGC		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000313

AC:

AN:

150120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000985

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000267

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000510

AC:

692

AN:

1356938

Hom.:

AF XY:

0.000496

AC XY:

332

AN XY:

669234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000701

Gnomad4 AMR exome

AF:

0.000475

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000263

Gnomad4 FIN exome

AF:

0.0000485

Gnomad4 NFE exome

AF:

0.000613

Gnomad4 OTH exome

AF:

0.000372

GnomAD4 genome

AF:

0.000313

AC:

AN:

150210

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

AN XY:

73326

show subpopulations

Gnomad4 AFR

AF:

0.000171

Gnomad4 AMR

AF:

0.00139

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000985

Gnomad4 NFE

AF:

0.000267

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 14, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ASCL1-related disorder

Benign:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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