12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCA

Variant names:

• chr12-102958393-CGCAGCAGCA-C
• rs3832799
• NM_004316.4:c.178_186delCAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_004316.4(ASCL1):​c.178_186delCAGCAGCAG​(p.Gln60_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 0.00312 in 1,507,038 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: ASCL1 NM_004316.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.809
• 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 -12 ACMG points.

• BP6: Variant 12-102958393-CGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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_186delCAGCAGCAG	p.Gln60_Gln62del	conservative_inframe_deletion	Exon 1 of 2	NP_004307.2
	PAH	NM_001354304.2		c.-303_-295delTGCTGCTGC		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_186delCAGCAGCAG	p.Gln60_Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENSP00000266744.3
	PAH	ENST00000547319.1	TSL:4	n.9_17delTGCTGCTGC		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-303_-295delTGCTGCTGC		upstream_gene	N/A	ENSP00000447620.1

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 399 AN: 150116 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

Gnomad ASJ AF: 0.00550

Gnomad EAS AF: 0.00178

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00585

GnomAD4 exome AF: 0.00317 AC: 4302 AN: 1356832 Hom.: 12 AF XY: 0.00330 AC XY: 2206 AN XY: 669160

African (AFR) AF: 0.00105 AC: 30 AN: 28512

American (AMR) AF: 0.00243 AC: 82 AN: 33680

Ashkenazi Jewish (ASJ) AF: 0.00537 AC: 129 AN: 24012

East Asian (EAS) AF: 0.000869 AC: 29 AN: 33378

South Asian (SAS) AF: 0.00951 AC: 722 AN: 75952

European-Finnish (FIN) AF: 0.00182 AC: 75 AN: 41208

Middle Eastern (MID) AF: 0.0108 AC: 44 AN: 4082

European-Non Finnish (NFE) AF: 0.00281 AC: 2977 AN: 1059544

Other (OTH) AF: 0.00379 AC: 214 AN: 56464

GnomAD4 genome AF: 0.00266 AC: 399 AN: 150206 Hom.: 2 Cov.: 0 AF XY: 0.00282 AC XY: 207 AN XY: 73324

African (AFR) AF: 0.000829 AC: 34 AN: 40994

American (AMR) AF: 0.00145 AC: 22 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00550 AC: 19 AN: 3456

East Asian (EAS) AF: 0.00178 AC: 9 AN: 5054

South Asian (SAS) AF: 0.0143 AC: 68 AN: 4760

European-Finnish (FIN) AF: 0.00227 AC: 23 AN: 10152

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.00312 AC: 210 AN: 67372

Other (OTH) AF: 0.00579 AC: 12 AN: 2072

Alfa AF: 0.00129 Hom.: 277

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=164/36	disease causing (fs/PTC)

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;