chr12-102958393-CGCAGCAGCAGCA-C

Variant names:

• chr12-102958393-CGCAGCAGCAGCA-C
• rs3832799
• NM_004316.4:c.175_186delCAGCAGCAGCAG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004316.4(ASCL1):​c.175_186delCAGCAGCAGCAG​(p.Gln59_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 0.000855 in 1,507,074 control chromosomes in the GnomAD database, including 4 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: ASCL1 NM_004316.4 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• 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), 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 12-102958393-CGCAGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCAGCA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 259284.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	NM_004316.4	MANE Select	c.175_186delCAGCAGCAGCAG	p.Gln59_Gln62del	conservative_inframe_deletion	Exon 1 of 2	NP_004307.2	P50553
	PAH	NM_001354304.2		c.-306_-295delTGCTGCTGCTGC		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.175_186delCAGCAGCAGCAG	p.Gln59_Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENSP00000266744.3	P50553
	PAH	ENST00000547319.1	TSL:4	n.6_17delTGCTGCTGCTGC		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-306_-295delTGCTGCTGCTGC		upstream_gene	N/A	ENSP00000447620.1	F8W0A0

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 222 AN: 150116 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00119

Gnomad ASJ AF: 0.00694

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.00210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000683

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.000787 AC: 1068 AN: 1356868 Hom.: 2 AF XY: 0.000844 AC XY: 565 AN XY: 669194

African (AFR) AF: 0.00253 AC: 72 AN: 28508

American (AMR) AF: 0.000802 AC: 27 AN: 33682

Ashkenazi Jewish (ASJ) AF: 0.00583 AC: 140 AN: 24000

East Asian (EAS) AF: 0.000839 AC: 28 AN: 33382

South Asian (SAS) AF: 0.00195 AC: 148 AN: 75972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41210

Middle Eastern (MID) AF: 0.00122 AC: 5 AN: 4084

European-Non Finnish (NFE) AF: 0.000541 AC: 573 AN: 1059564

Other (OTH) AF: 0.00133 AC: 75 AN: 56466

GnomAD4 genome AF: 0.00147 AC: 221 AN: 150206 Hom.: 2 Cov.: 0 AF XY: 0.00162 AC XY: 119 AN XY: 73322

African (AFR) AF: 0.00290 AC: 119 AN: 40992

American (AMR) AF: 0.00119 AC: 18 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00694 AC: 24 AN: 3456

East Asian (EAS) AF: 0.000396 AC: 2 AN: 5054

South Asian (SAS) AF: 0.00189 AC: 9 AN: 4760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10154

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

European-Non Finnish (NFE) AF: 0.000683 AC: 46 AN: 67372

Other (OTH) AF: 0.00145 AC: 3 AN: 2072

Alfa AF: 0.00 Hom.: 277

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ASCL1-related disorder (1)
-	-	1	Phenylketonuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=160/40	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;