chr12-102958871-C-G

Variant names:

• chr12-102958871-C-G
• rs731682
• NM_004316.4:c.627C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004316.4(ASCL1):​c.627C>G​(p.Val209Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 1,613,968 control chromosomes in the GnomAD database, including 3,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (1043 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2664 hom.)
• Consequence: ASCL1 NM_004316.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.17
• Publications: 8 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]

ASCL1 Gene-Disease associations (from GenCC):

• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 12-102958871-C-G is Benign according to our data. Variant chr12-102958871-C-G is described in ClinVar as Benign. ClinVar VariationId is 162758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 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.627C>G	p.Val209Val	synonymous	Exon 1 of 2	NP_004307.2	P50553

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.627C>G	p.Val209Val	synonymous	Exon 1 of 2	ENSP00000266744.3	P50553

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 13237 AN: 152204 Hom.: 1037 Cov.: 33

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0349

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0512

Gnomad OTH AF: 0.0694

GnomAD2 exomes AF: 0.0491 AC: 12147 AN: 247292 AF XY: 0.0462

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.000166

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0514

Gnomad OTH exome AF: 0.0413

GnomAD4 exome AF: 0.0524 AC: 76621 AN: 1461646 Hom.: 2664 Cov.: 35 AF XY: 0.0513 AC XY: 37338 AN XY: 727130

African (AFR) AF: 0.208 AC: 6953 AN: 33474

American (AMR) AF: 0.0273 AC: 1222 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2676 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0243 AC: 2097 AN: 86244

European-Finnish (FIN) AF: 0.0201 AC: 1072 AN: 53252

Middle Eastern (MID) AF: 0.0600 AC: 346 AN: 5768

European-Non Finnish (NFE) AF: 0.0532 AC: 59119 AN: 1111962

Other (OTH) AF: 0.0518 AC: 3131 AN: 60394

GnomAD4 genome AF: 0.0871 AC: 13262 AN: 152322 Hom.: 1043 Cov.: 33 AF XY: 0.0837 AC XY: 6234 AN XY: 74490

African (AFR) AF: 0.202 AC: 8399 AN: 41552

American (AMR) AF: 0.0349 AC: 534 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4830

European-Finnish (FIN) AF: 0.0174 AC: 185 AN: 10630

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0512 AC: 3486 AN: 68040

Other (OTH) AF: 0.0682 AC: 144 AN: 2112

Alfa AF: 0.0654 Hom.: 134

Bravo AF: 0.0954

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0509

EpiControl AF: 0.0546

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.9
DANN	Benign	0.84
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs731682; hg19: chr12-103352649; COSMIC: COSV57150907;