12-102958393-CGCAGCAGCAGCAGCAGCAGCA-C

Position:

• chr12-102958393-CGCAGCAGCAGCAGCAGCAGCA-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004316.4(ASCL1):​c.166_186del​(p.Gln56_Gln62del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,507,080 control chromosomes in the GnomAD database, including 7 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: ASCL1 NM_004316.4 inframe_deletion
• Clinical Significance: Not reported in ClinVar
• 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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 258 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.166_186del	p.Gln56_Gln62del	inframe_deletion	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-315_-295del		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.166_186del	p.Gln56_Gln62del	inframe_deletion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1			non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 258 AN: 150116 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000595

Gnomad ASJ AF: 0.000579

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00399

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.00193 AC: 2614 AN: 1356874 Hom.: 7 AF XY: 0.00196 AC XY: 1314 AN XY: 669192

Gnomad4 AFR exome AF: 0.000456

Gnomad4 AMR exome AF: 0.000445

Gnomad4 ASJ exome AF: 0.000416

Gnomad4 EAS exome AF: 0.0000300

Gnomad4 SAS exome AF: 0.00312

Gnomad4 FIN exome AF: 0.00306

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00172 AC: 258 AN: 150206 Hom.: 0 Cov.: 0 AF XY: 0.00162 AC XY: 119 AN XY: 73324

Gnomad4 AFR AF: 0.000756

Gnomad4 AMR AF: 0.000594

Gnomad4 ASJ AF: 0.000579

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00399

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00145

ClinVar

Not reported in ClinVar

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;