12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Position:

• chr12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004316.4(ASCL1):​c.184_186dup​(p.Gln62dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6824 hom., cov: 0)
  • Exomes 𝑓: 0.25 (7829 hom.)
• Consequence: ASCL1 NM_004316.4 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.219

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]

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]

ACMG classification

Verdict is Benign. Variant got -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 [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/exons	MANE	UniProt
ASCL1	NM_004316.4	c.184_186dup	p.Gln62dup	inframe_insertion	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-295_-294insTGC		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.184_186dup	p.Gln62dup	inframe_insertion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1	n.17_18insTGC		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.298 AC: 44662 AN: 150016 Hom.: 6816 Cov.: 0

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.: 17 AF XY: 0.251 AC XY: 167995 AN XY: 668640

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.0207

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.239

GnomAD4 genome AF: 0.298 AC: 44690 AN: 150104 Hom.: 6824 Cov.: 0 AF XY: 0.295 AC XY: 21630 AN XY: 73270

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.289

Gnomad4 EAS AF: 0.0257

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.292

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 04, 2014	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). -
Benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3832799; hg19: chr12-103352171;