12-102958393-CGCAGCAGCAGCAGCA-C

Position:

• chr12-102958393-CGCAGCAGCAGCAGCA-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004316.4(ASCL1):​c.172_186del​(p.Gln58_Gln62del) variant causes a 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. 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 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:5
• Conservation: PhyloP100: 0.809

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 Likely_benign. Variant got -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. Variant chr12-102958393-CGCAGCAGCAGCAGCA-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 437 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.172_186del	p.Gln58_Gln62del	inframe_deletion	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-309_-295del		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.172_186del	p.Gln58_Gln62del	inframe_deletion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1	n.3_17del		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 437 AN: 150120 Hom.: 1 Cov.: 0

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.: 9 AF XY: 0.00423 AC XY: 2831 AN XY: 669150

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00452

Gnomad4 ASJ exome AF: 0.000208

Gnomad4 EAS exome AF: 0.0000300

Gnomad4 SAS exome AF: 0.00323

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00490

Gnomad4 OTH exome AF: 0.00377

GnomAD4 genome AF: 0.00291 AC: 437 AN: 150210 Hom.: 1 Cov.: 0 AF XY: 0.00288 AC XY: 211 AN XY: 73326

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00376

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00273

Gnomad4 FIN AF: 0.000985

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00290

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 22, 2015

- -

ASCL1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2023

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

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;