12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_004316.4(ASCL1):c.184_186delCAG(p.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 0.024 in 1,297,614 control chromosomes in the GnomAD database, including 46 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.011 ( 7 hom., cov: 0)

Exomes 𝑓: 0.026 ( 39 hom. )

Consequence

ASCL1
NM_004316.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 -10 ACMG points.

BP6

Variant 12-102958393-CGCA-C is Benign according to our data. Variant chr12-102958393-CGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 227179.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0106 (1589/150014) while in subpopulation SAS AF = 0.0269 (128/4756). AF 95% confidence interval is 0.0231. There are 7 homozygotes in GnomAd4. There are 831 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.184_186delCAG	p.Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-297_-295delTGC		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_186delCAG	p.Gln62del	conservative_inframe_deletion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.15_17delTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-297_-295delTGC		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0
PAH	ENST00000635500.1 link	n.-174_-172delTGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1587

AN:

149932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.00111

Gnomad AMR

AF:

0.00893

Gnomad ASJ

AF:

0.00492

Gnomad EAS

AF:

0.00355

Gnomad SAS

AF:

0.0266

Gnomad FIN

AF:

0.0126

Gnomad MID

AF:

0.0192

Gnomad NFE

AF:

0.00827

Gnomad OTH

AF:

0.0137

GnomAD4 exome

AF:

0.0257

AC:

29494

AN:

1147600

Hom.:

AF XY:

0.0276

AC XY:

15525

AN XY:

562096

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0258

AC:

666

AN:

25834

American (AMR)

AF:

0.0558

AC:

1516

AN:

27170

Ashkenazi Jewish (ASJ)

AF:

0.0299

AC:

583

AN:

19516

East Asian (EAS)

AF:

0.0334

AC:

751

AN:

22460

South Asian (SAS)

AF:

0.0808

AC:

4764

AN:

58930

European-Finnish (FIN)

AF:

0.0339

AC:

1137

AN:

33500

Middle Eastern (MID)

AF:

0.0287

AC:

101

AN:

3520

European-Non Finnish (NFE)

AF:

0.0205

AC:

18662

AN:

910284

Other (OTH)

AF:

0.0283

AC:

1314

AN:

46386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.346

Heterozygous variant carriers

2526

5052

7577

10103

12629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0106

AC:

1589

AN:

150014

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

831

AN XY:

73218

show subpopulations

African (AFR)

AF:

0.0139

AC:

571

AN:

40980

American (AMR)

AF:

0.00892

AC:

135

AN:

15132

Ashkenazi Jewish (ASJ)

AF:

0.00492

AC:

AN:

3452

East Asian (EAS)

AF:

0.00357

AC:

AN:

5048

South Asian (SAS)

AF:

0.0269

AC:

128

AN:

4756

European-Finnish (FIN)

AF:

0.0126

AC:

127

AN:

10082

Middle Eastern (MID)

AF:

0.0207

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00828

AC:

557

AN:

67308

Other (OTH)

AF:

0.0141

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0538

Hom.:

277

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

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[11] in exon 1 of ASCL1: This variant is not expected to have clinical sign ificance because it has been identified in 2.2% (7/322) of Caucasian control chr omosomes (Deng 2010) and has been identified by our laboratory in 1.6% (5/304) o f Caucasian control chromosomes. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.22

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCA

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