12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCA

Position:

• chr12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_004316.4(ASCL1):​c.178_186del​(p.Gln60_Gln62del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,507,038 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: ASCL1 NM_004316.4 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -12 ACMG points.

• BP6: Variant 12-102958393-CGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCA-C is described in ClinVar as [Benign]. Clinvar id is 259285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102958393-CGCAGCAGCA-C is described in Lovd as [Likely_benign]. Variant chr12-102958393-CGCAGCAGCA-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 399 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.178_186del	p.Gln60_Gln62del	inframe_deletion	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-303_-295del		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.178_186del	p.Gln60_Gln62del	inframe_deletion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1	n.9_17del		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 399 AN: 150116 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

Gnomad ASJ AF: 0.00550

Gnomad EAS AF: 0.00178

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00585

GnomAD4 exome AF: 0.00317 AC: 4302 AN: 1356832 Hom.: 12 AF XY: 0.00330 AC XY: 2206 AN XY: 669160

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00243

Gnomad4 ASJ exome AF: 0.00537

Gnomad4 EAS exome AF: 0.000869

Gnomad4 SAS exome AF: 0.00951

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00281

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.00266 AC: 399 AN: 150206 Hom.: 2 Cov.: 0 AF XY: 0.00282 AC XY: 207 AN XY: 73324

Gnomad4 AFR AF: 0.000829

Gnomad4 AMR AF: 0.00145

Gnomad4 ASJ AF: 0.00550

Gnomad4 EAS AF: 0.00178

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.00227

Gnomad4 NFE AF: 0.00312

Gnomad4 OTH AF: 0.00579

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	ASCL1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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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;