12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCA

Position:

• chr12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCA

Variant summary

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

The NM_004316.4(ASCL1):​c.181_186del​(p.Gln61_Gln62del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,506,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: ASCL1 NM_004316.4 inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.692

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-CGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCA-C is described in ClinVar as [Benign]. Clinvar id is 1686519.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-102958393-CGCAGCA-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.181_186del	p.Gln61_Gln62del	inframe_deletion	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-300_-295del		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.181_186del	p.Gln61_Gln62del	inframe_deletion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1	n.12_17del		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000926 AC: 139 AN: 150116 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000595

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.000975

GnomAD4 exome AF: 0.000431 AC: 585 AN: 1355898 Hom.: 0 AF XY: 0.000408 AC XY: 273 AN XY: 668644

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000125

Gnomad4 EAS exome AF: 0.000390

Gnomad4 SAS exome AF: 0.000515

Gnomad4 FIN exome AF: 0.000170

Gnomad4 NFE exome AF: 0.000332

Gnomad4 OTH exome AF: 0.000798

GnomAD4 genome AF: 0.000925 AC: 139 AN: 150206 Hom.: 0 Cov.: 0 AF XY: 0.000846 AC XY: 62 AN XY: 73322

Gnomad4 AFR AF: 0.00246

Gnomad4 AMR AF: 0.000594

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000630

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000356

Gnomad4 OTH AF: 0.000965

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

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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;