NM_004316.4:c.178_186dupCAGCAGCAG

Variant names:

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

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.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
• 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: Benign. The variant received -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 VariationId 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.

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

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.178_186dupCAGCAGCAG	p.Gln60_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENSP00000266744.3
	PAH	ENST00000547319.1	TSL:4	n.9_17dupTGCTGCTGC		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-303_-295dupTGCTGCTGC		upstream_gene	N/A	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

African (AFR) AF: 0.0518 AC: 1475 AN: 28476

American (AMR) AF: 0.0243 AC: 818 AN: 33674

Ashkenazi Jewish (ASJ) AF: 0.0281 AC: 674 AN: 24000

East Asian (EAS) AF: 0.168 AC: 5606 AN: 33346

South Asian (SAS) AF: 0.0397 AC: 3014 AN: 75962

European-Finnish (FIN) AF: 0.00349 AC: 144 AN: 41214

Middle Eastern (MID) AF: 0.0216 AC: 88 AN: 4078

European-Non Finnish (NFE) AF: 0.00872 AC: 9239 AN: 1059346

Other (OTH) AF: 0.0251 AC: 1417 AN: 56450

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

African (AFR) AF: 0.0507 AC: 2077 AN: 40974

American (AMR) AF: 0.0221 AC: 335 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 82 AN: 3456

East Asian (EAS) AF: 0.170 AC: 858 AN: 5050

South Asian (SAS) AF: 0.0481 AC: 229 AN: 4758

European-Finnish (FIN) AF: 0.00295 AC: 30 AN: 10154

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00919 AC: 619 AN: 67368

Other (OTH) AF: 0.0294 AC: 61 AN: 2072

Alfa AF: 0.00963 Hom.: 277

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=79/21	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: COSV57151174;