NM_004316.4:c.184_186dupCAG

Variant names:

• chr12-102958393-C-CGCA
• rs3832799
• NM_004316.4:c.184_186dupCAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004316.4(ASCL1):​c.184_186dupCAG​(p.Gln62dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6824 hom., cov: 0)
  • Exomes 𝑓: 0.25 (7829 hom.)
• Consequence: ASCL1 NM_004316.4 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.219
• 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), ClinGen, Myriad Women’s Health, G2P
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-102958393-C-CGCA is Benign according to our data. Variant chr12-102958393-C-CGCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004316.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	NM_004316.4	MANE Select	c.184_186dupCAG	p.Gln62dup	conservative_inframe_insertion	Exon 1 of 2	NP_004307.2	P50553
	PAH	NM_001354304.2		c.-297_-295dupTGC		5_prime_UTR	Exon 1 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.184_186dupCAG	p.Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENSP00000266744.3	P50553
	PAH	ENST00000547319.1	TSL:4	n.15_17dupTGC		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-297_-295dupTGC		upstream_gene	N/A	ENSP00000447620.1	F8W0A0

Frequencies

GnomAD3 genomes AF: 0.298 AC: 44662 AN: 150016 Hom.: 6816 Cov.: 0

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.311

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.295

GnomAD4 exome AF: 0.254 AC: 344547 AN: 1355720 Hom.: 7829 Cov.: 17 AF XY: 0.251 AC XY: 167995 AN XY: 668640

African (AFR) AF: 0.284 AC: 8076 AN: 28454

American (AMR) AF: 0.206 AC: 6913 AN: 33598

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6064 AN: 23996

East Asian (EAS) AF: 0.0207 AC: 690 AN: 33368

South Asian (SAS) AF: 0.156 AC: 11864 AN: 75884

European-Finnish (FIN) AF: 0.285 AC: 11746 AN: 41148

Middle Eastern (MID) AF: 0.288 AC: 1175 AN: 4076

European-Non Finnish (NFE) AF: 0.269 AC: 284531 AN: 1058786

Other (OTH) AF: 0.239 AC: 13488 AN: 56410

GnomAD4 genome AF: 0.298 AC: 44690 AN: 150104 Hom.: 6824 Cov.: 0 AF XY: 0.295 AC XY: 21630 AN XY: 73270

African (AFR) AF: 0.332 AC: 13592 AN: 40956

American (AMR) AF: 0.252 AC: 3811 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 996 AN: 3452

East Asian (EAS) AF: 0.0257 AC: 130 AN: 5054

South Asian (SAS) AF: 0.159 AC: 755 AN: 4758

European-Finnish (FIN) AF: 0.362 AC: 3677 AN: 10148

Middle Eastern (MID) AF: 0.317 AC: 92 AN: 290

European-Non Finnish (NFE) AF: 0.308 AC: 20727 AN: 67324

Other (OTH) AF: 0.292 AC: 605 AN: 2072

Alfa AF: 0.197 Hom.: 277

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=79/21	polymorphism (auto)

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: COSV57150798; COSMIC: COSV57150798;