12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chr12-102958393-CGCAGCA-C
• rs3832799
• NM_004316.4:c.181_186delCAGCAG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004316.4(ASCL1):​c.181_186delCAGCAG​(p.Gln61_Gln62del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.692
• Publications: 15 publications found

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]

PAH Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4	c.181_186delCAGCAG	p.Gln61_Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENST00000266744.4	NP_004307.2
PAH	NM_001354304.2	c.-300_-295delTGCTGC		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.181_186delCAGCAG	p.Gln61_Gln62del	conservative_inframe_deletion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3
PAH	ENST00000547319.1	n.12_17delTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5	c.-300_-295delTGCTGC		upstream_gene_variant		3		ENSP00000447620.1
PAH	ENST00000635500.1	n.-177_-172delTGCTGC		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

African (AFR) AF: 0.00302 AC: 86 AN: 28498

American (AMR) AF: 0.00110 AC: 37 AN: 33600

Ashkenazi Jewish (ASJ) AF: 0.000125 AC: 3 AN: 24004

East Asian (EAS) AF: 0.000390 AC: 13 AN: 33340

South Asian (SAS) AF: 0.000515 AC: 39 AN: 75752

European-Finnish (FIN) AF: 0.000170 AC: 7 AN: 41142

Middle Eastern (MID) AF: 0.000735 AC: 3 AN: 4080

European-Non Finnish (NFE) AF: 0.000332 AC: 352 AN: 1059064

Other (OTH) AF: 0.000798 AC: 45 AN: 56418

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

African (AFR) AF: 0.00246 AC: 101 AN: 40994

American (AMR) AF: 0.000594 AC: 9 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.000630 AC: 3 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000356 AC: 24 AN: 67370

Other (OTH) AF: 0.000965 AC: 2 AN: 2072

Alfa AF: 0.00 Hom.: 277

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69
Mutation Taster		=178/22	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3832799; hg19: chr12-103352171; COSMIC: COSV106053219; COSMIC: COSV106053219;