12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_004316.4(ASCL1):c.181_186dupCAGCAG(p.Gln61_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 0.021 ( 50 hom., cov: 0)

Exomes 𝑓: 0.012 ( 11 hom. )

Consequence

ASCL1
NM_004316.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

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-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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 50 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.181_186dupCAGCAG	p.Gln61_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-300_-295dupTGCTGC		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.181_186dupCAGCAG	p.Gln61_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.12_17dupTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-300_-295dupTGCTGC		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0
PAH	ENST00000635500.1 link	n.-177_-172dupTGCTGC		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

African (AFR)

AF:

0.0485

AC:

1379

AN:

28450

American (AMR)

AF:

0.0103

AC:

347

AN:

33672

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

AN:

24010

East Asian (EAS)

AF:

0.00730

AC:

238

AN:

32588

South Asian (SAS)

AF:

0.00993

AC:

753

AN:

75866

European-Finnish (FIN)

AF:

0.00250

AC:

103

AN:

41208

Middle Eastern (MID)

AF:

0.0150

AC:

AN:

4078

European-Non Finnish (NFE)

AF:

0.0116

AC:

12290

AN:

1059362

Other (OTH)

AF:

0.0130

AC:

732

AN:

56400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

883

1766

2649

3532

4415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0211

AC:

3170

AN:

150202

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1489

AN XY:

73322

show subpopulations

African (AFR)

AF:

0.0501

AC:

2054

AN:

40988

American (AMR)

AF:

0.0139

AC:

210

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00550

AC:

AN:

3456

East Asian (EAS)

AF:

0.00257

AC:

AN:

5054

South Asian (SAS)

AF:

0.00903

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.00315

AC:

AN:

10154

Middle Eastern (MID)

AF:

0.0276

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0111

AC:

749

AN:

67370

Other (OTH)

AF:

0.0183

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

149

299

448

598

747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00730

Hom.:

277

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

Sep 25, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

PhyloP100

0.22

Mutation Taster

=79/21

polymorphism

(source)

Splicing

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

Publications

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12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

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