chr12-102958393-C-CGCAGCA

Variant names:

• chr12-102958393-C-CGCAGCA
• rs3832799
• NM_004316.4:c.181_186dupCAGCAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004316.4(ASCL1):​c.181_186dupCAGCAG​(p.Gln61_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 0.021 (50 hom., cov: 0)
  • Exomes 𝑓: 0.012 (11 hom.)
• Consequence: ASCL1 NM_004316.4 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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-CGCAGCA is Benign according to our data. Variant chr12-102958393-C-CGCAGCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0211 (3170/150202) while in subpopulation AFR AF = 0.0501 (2054/40988). AF 95% confidence interval is 0.0483. There are 50 homozygotes in GnomAd4. There are 1489 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 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.181_186dupCAGCAG	p.Gln61_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	NP_004307.2
	PAH	NM_001354304.2		c.-300_-295dupTGCTGC		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.181_186dupCAGCAG	p.Gln61_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENSP00000266744.3
	PAH	ENST00000547319.1	TSL:4	n.12_17dupTGCTGC		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-300_-295dupTGCTGC		upstream_gene	N/A	ENSP00000447620.1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3161 AN: 150112 Hom.: 51 Cov.: 0

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00443

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00550

Gnomad EAS AF: 0.00256

Gnomad SAS AF: 0.00902

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.0321

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0185

GnomAD4 exome AF: 0.0118 AC: 15996 AN: 1355634 Hom.: 11 Cov.: 17 AF XY: 0.0117 AC XY: 7823 AN XY: 668578

African (AFR) AF: 0.0485 AC: 1379 AN: 28450

American (AMR) AF: 0.0103 AC: 347 AN: 33672

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 93 AN: 24010

East Asian (EAS) AF: 0.00730 AC: 238 AN: 32588

South Asian (SAS) AF: 0.00993 AC: 753 AN: 75866

European-Finnish (FIN) AF: 0.00250 AC: 103 AN: 41208

Middle Eastern (MID) AF: 0.0150 AC: 61 AN: 4078

European-Non Finnish (NFE) AF: 0.0116 AC: 12290 AN: 1059362

Other (OTH) AF: 0.0130 AC: 732 AN: 56400

GnomAD4 genome AF: 0.0211 AC: 3170 AN: 150202 Hom.: 50 Cov.: 0 AF XY: 0.0203 AC XY: 1489 AN XY: 73322

African (AFR) AF: 0.0501 AC: 2054 AN: 40988

American (AMR) AF: 0.0139 AC: 210 AN: 15154

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

East Asian (EAS) AF: 0.00257 AC: 13 AN: 5054

South Asian (SAS) AF: 0.00903 AC: 43 AN: 4762

European-Finnish (FIN) AF: 0.00315 AC: 32 AN: 10154

Middle Eastern (MID) AF: 0.0276 AC: 8 AN: 290

European-Non Finnish (NFE) AF: 0.0111 AC: 749 AN: 67370

Other (OTH) AF: 0.0183 AC: 38 AN: 2072

Alfa AF: 0.00730 Hom.: 277

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

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: COSV105074389; COSMIC: COSV105074389;