12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_004316.4(ASCL1):c.178_186delCAGCAGCAG(p.Gln60_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 0.00312 in 1,507,038 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0032 ( 12 hom. )

Consequence

ASCL1
NM_004316.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

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 Benign. Variant got -12 ACMG points.

BP6

Variant 12-102958393-CGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 259285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102958393-CGCAGCAGCA-C is described in Lovd as [Likely_benign]. Variant chr12-102958393-CGCAGCAGCA-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 399 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.178_186delCAGCAGCAG	p.Gln60_Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-303_-295delTGCTGCTGC		5_prime_UTR_variant	Exon 1 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ASCL1	ENST00000266744.4 link	c.178_186delCAGCAGCAG	p.Gln60_Gln62del	conservative_inframe_deletion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.9_17delTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-303_-295delTGCTGCTGC		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0

Frequencies

GnomAD3 genomes

AF:

0.00266

AC:

399

AN:

150116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000832

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00145

Gnomad ASJ

AF:

0.00550

Gnomad EAS

AF:

0.00178

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00227

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.00312

Gnomad OTH

AF:

0.00585

GnomAD4 exome

AF:

0.00317

AC:

4302

AN:

1356832

Hom.:

AF XY:

0.00330

AC XY:

2206

AN XY:

669160

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00243

Gnomad4 ASJ exome

AF:

0.00537

Gnomad4 EAS exome

AF:

0.000869

Gnomad4 SAS exome

AF:

0.00951

Gnomad4 FIN exome

AF:

0.00182

Gnomad4 NFE exome

AF:

0.00281

Gnomad4 OTH exome

AF:

0.00379

GnomAD4 genome

AF:

0.00266

AC:

399

AN:

150206

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

207

AN XY:

73324

show subpopulations

Gnomad4 AFR

AF:

0.000829

Gnomad4 AMR

AF:

0.00145

Gnomad4 ASJ

AF:

0.00550

Gnomad4 EAS

AF:

0.00178

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.00227

Gnomad4 NFE

AF:

0.00312

Gnomad4 OTH

AF:

0.00579

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ASCL1: BS2 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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