12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004316.4(ASCL1):c.184_186dupCAG(p.Gln62dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 6824 hom., cov: 0)

Exomes 𝑓: 0.25 ( 7829 hom. )

Consequence

ASCL1
NM_004316.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.219

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 12-102958393-C-CGCA is Benign according to our data. Variant chr12-102958393-C-CGCA is described in ClinVar as [Likely_benign]. Clinvar id is 179366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.184_186dupCAG	p.Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-297_-295dupTGC		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.184_186dupCAG	p.Gln62dup	conservative_inframe_insertion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.15_17dupTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-297_-295dupTGC		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0
PAH	ENST00000635500.1 link	n.-174_-172dupTGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

44662

AN:

150016

Hom.:

6816

Cov.:

show subpopulations

Gnomad AFR

AF:

0.332

Gnomad AMI

AF:

0.338

Gnomad AMR

AF:

0.251

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.0258

Gnomad SAS

AF:

0.158

Gnomad FIN

AF:

0.362

Gnomad MID

AF:

0.311

Gnomad NFE

AF:

0.308

Gnomad OTH

AF:

0.295

GnomAD4 exome

AF:

0.254

AC:

344547

AN:

1355720

Hom.:

7829

Cov.:

AF XY:

0.251

AC XY:

167995

AN XY:

668640

show subpopulations

African (AFR)

AF:

0.284

AC:

8076

AN:

28454

American (AMR)

AF:

0.206

AC:

6913

AN:

33598

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6064

AN:

23996

East Asian (EAS)

AF:

0.0207

AC:

690

AN:

33368

South Asian (SAS)

AF:

0.156

AC:

11864

AN:

75884

European-Finnish (FIN)

AF:

0.285

AC:

11746

AN:

41148

Middle Eastern (MID)

AF:

0.288

AC:

1175

AN:

4076

European-Non Finnish (NFE)

AF:

0.269

AC:

284531

AN:

1058786

Other (OTH)

AF:

0.239

AC:

13488

AN:

56410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

17012

34025

51037

68050

85062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.298

AC:

44690

AN:

150104

Hom.:

6824

Cov.:

AF XY:

0.295

AC XY:

21630

AN XY:

73270

show subpopulations

African (AFR)

AF:

0.332

AC:

13592

AN:

40956

American (AMR)

AF:

0.252

AC:

3811

AN:

15148

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

996

AN:

3452

East Asian (EAS)

AF:

0.0257

AC:

130

AN:

5054

South Asian (SAS)

AF:

0.159

AC:

755

AN:

4758

European-Finnish (FIN)

AF:

0.362

AC:

3677

AN:

10148

Middle Eastern (MID)

AF:

0.317

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.308

AC:

20727

AN:

67324

Other (OTH)

AF:

0.292

AC:

605

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1519

3038

4556

6075

7594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.197

Hom.:

277

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Dec 12, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 31, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 04, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gln51[13] in exon 1 of ASCL1: This variant is not expected to have clinical sig nificance because it has been identified at high frequencies in published contro l chromosomes, including 1.3% (24/1804) of Japanese chromosomes (Sasaki 2003, Id e 2005) and 13% (42/322) of Caucasian chromosomes (Deng 2010). Moreover, Gln51[1 3] has been identified by our laboratory in 32% (96/304) of Caucasian control ch romosomes (LMM unpublished data). -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

African/African American population allele frequency is 31.43% (rs3832799, 2696/8308 alleles, 431 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

not provided

Benign:1

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.22

Mutation Taster

=79/21

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over