12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_004316.4(ASCL1):c.172_186delCAGCAGCAGCAGCAG(p.Gln58_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 0.0042 in 1,507,022 control chromosomes in the GnomAD database, including 10 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0043 ( 9 hom. )

Consequence

ASCL1
NM_004316.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:5

Conservation

PhyloP100: 0.809

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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 12-102958393-CGCAGCAGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCAGCAGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 193277.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.172_186delCAGCAGCAGCAGCAG	p.Gln58_Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-309_-295delTGCTGCTGCTGCTGC		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.172_186delCAGCAGCAGCAGCAG	p.Gln58_Gln62del	conservative_inframe_deletion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.3_17delTGCTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-309_-295delTGCTGCTGCTGCTGC		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0
PAH	ENST00000635500.1 link	n.-186_-172delTGCTGCTGCTGCTGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

437

AN:

150120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00377

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00273

Gnomad FIN

AF:

0.000985

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.00292

GnomAD4 exome

AF:

0.00435

AC:

5896

AN:

1356812

Hom.:

AF XY:

0.00423

AC XY:

2831

AN XY:

669150

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

28512

American (AMR)

AF:

0.00452

AC:

152

AN:

33664

Ashkenazi Jewish (ASJ)

AF:

0.000208

AC:

AN:

24016

East Asian (EAS)

AF:

0.0000300

AC:

AN:

33382

South Asian (SAS)

AF:

0.00323

AC:

245

AN:

75966

European-Finnish (FIN)

AF:

0.00119

AC:

AN:

41206

Middle Eastern (MID)

AF:

0.000979

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.00490

AC:

5192

AN:

1059520

Other (OTH)

AF:

0.00377

AC:

213

AN:

56462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

282

564

847

1129

1411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00291

AC:

437

AN:

150210

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

211

AN XY:

73326

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

40994

American (AMR)

AF:

0.00376

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5054

South Asian (SAS)

AF:

0.00273

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.000985

AC:

AN:

10154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00426

AC:

287

AN:

67372

Other (OTH)

AF:

0.00290

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

277

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ASCL1 p.Gln58_Gln62del variant was not identified in the literature but was identified in dbSNP (ID: rs3832799), ClinVar (classified as likely benign by PreventionGenetics and EGL Genetic Diagnostics), and LOVD 3.0 (classified as likely benign by VKGL-NL_Rotterdam and VKGL-NL_Groningen). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). This variant is an in-frame deletion resulting in the removal of a string of glutamine (gln) residues from codons 58-62; this deletion is found within a glutamine repeat region and is not expected to have a functional impact. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

not specified

Benign:1

Jan 22, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ASCL1-related disorder

Benign:1

Feb 03, 2023

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

PhyloP100

0.81

Mutation Taster

=171/29

disease causing (fs/PTC)

(source)

Splicing

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

Publications

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12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCA

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