12-102958871-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.17

Publications

8 publications found

Variant links:

COSMIC-nc: COSV57150907

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

ASCL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.627C>G	p.Val209Val	synonymous_variant	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASCL1	ENST00000266744.4 link	c.627C>G	p.Val209Val	synonymous_variant	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3		P50553

Frequencies

GnomAD3 genomes

AF:

0.0870

AC:

13237

AN:

152204

Hom.:

1037

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0513

AC XY:

37338

AN XY:

727130

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4830

9660

14491

19321

24151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2308

4616

6924

9232

11540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0871

AC:

13262

AN:

152322

Hom.:

1043

Cov.:

AF XY:

0.0837

AC XY:

6234

AN XY:

74490

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0512

AC:

3486

AN:

68040

Other (OTH)

AF:

0.0682

AC:

144

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

589

1178

1768

2357

2946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0654

Hom.:

134

Bravo

AF:

0.0954

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0509

EpiControl

AF:

0.0546

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val209Val in exon 1 of ASCL1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 20.1% (887/4402) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs731682). -

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.9

(source)

DANN

Benign

0.84

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over