chr12-102958393-C-CGCAGCAGCA

Variant names:

• chr12-102958393-C-CGCAGCAGCA
• rs3832799
• NM_004316.4:c.178_186dupCAGCAGCAG

Variant summary

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

The NM_004316.4(ASCL1):​c.178_186dupCAGCAGCAG​(p.Gln60_Gln62dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (129 hom., cov: 0)
  • Exomes 𝑓: 0.017 (65 hom.)
• Consequence: ASCL1 NM_004316.4 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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-CGCAGCAGCA is Benign according to our data. Variant chr12-102958393-C-CGCAGCAGCA is described in ClinVar as [Benign]. Clinvar id is 162757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4	c.178_186dupCAGCAGCAG	p.Gln60_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000266744.4	NP_004307.2
PAH	NM_001354304.2	c.-303_-295dupTGCTGCTGC		5_prime_UTR_variant	Exon 1 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASCL1	ENST00000266744.4	c.178_186dupCAGCAGCAG	p.Gln60_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3
PAH	ENST00000547319.1	n.9_17dupTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5	c.-303_-295dupTGCTGCTGC		upstream_gene_variant		3		ENSP00000447620.1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4297 AN: 150084 Hom.: 129 Cov.: 0

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.00295

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00919

Gnomad OTH AF: 0.0302

GnomAD4 exome AF: 0.0166 AC: 22475 AN: 1356546 Hom.: 65 Cov.: 17 AF XY: 0.0171 AC XY: 11411 AN XY: 669058

Gnomad4 AFR exome AF: 0.0518

Gnomad4 AMR exome AF: 0.0243

Gnomad4 ASJ exome AF: 0.0281

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.0397

Gnomad4 FIN exome AF: 0.00349

Gnomad4 NFE exome AF: 0.00872

Gnomad4 OTH exome AF: 0.0251

GnomAD4 genome AF: 0.0286 AC: 4294 AN: 150174 Hom.: 129 Cov.: 0 AF XY: 0.0296 AC XY: 2172 AN XY: 73306

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.0237

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.0481

Gnomad4 FIN AF: 0.00295

Gnomad4 NFE AF: 0.00919

Gnomad4 OTH AF: 0.0294

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gln51[15] in exon 1 of ASCL1: This variant is not expected to have clinical sign ificance because it has been reported in 19% (300/1604) of Japanese chromosomes (Ide 2005) and has been identified in 1.6% (5/304) of Caucasian control chromoso mes tested by our laboratory. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 14566559, 16021468, 20097173) -

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;