Genetic Variant NM_017988.6:c.177+35C>A (chr12-100283182-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017988.6(SCYL2):c.177+35C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,530,252 control chromosomes in the GnomAD database, including 32,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4337 hom., cov: 32)

Exomes 𝑓: 0.20 ( 27985 hom. )

Consequence

SCYL2
NM_017988.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.35

Publications

7 publications found

Variant links:

Genes affected

SCYL2 (HGNC:19286): (SCY1 like pseudokinase 2) The protein encoded by this gene associates with clathrin-coated complexes at the plasma membrane and with endocytic coated vesicles. The encoded protein phosphorylates the beta2 subunit of the plasma membrane adapter complex AP2 and interacts with clathrin, showing involvement in clathrin-dependent pathways between the trans-Golgi network and the endosomal system. In addition, this protein has a role in the Wnt signaling pathway by targeting frizzled 5 (Fzd5) for lysosomal degradation. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2015]

SCYL2 Gene-Disease associations (from GenCC):

arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

SCYL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 12-100283182-C-A is Benign according to our data. Variant chr12-100283182-C-A is described in ClinVar as Benign. ClinVar VariationId is 1332927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017988.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCYL2	NM_017988.6	MANE Select	c.177+35C>A	intron	N/A	NP_060458.3
SCYL2	NM_001330253.2		c.177+35C>A	intron	N/A	NP_001317182.1	A0A0U1RQQ9
SCYL2	NM_001330254.2		c.177+35C>A	intron	N/A	NP_001317183.1	A0A0U1RQQ9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCYL2	ENST00000360820.7	TSL:1 MANE Select	c.177+35C>A	intron	N/A	ENSP00000354061.2	Q6P3W7
SCYL2	ENST00000930683.1		c.177+35C>A	intron	N/A	ENSP00000600742.1
SCYL2	ENST00000635101.1	TSL:5	c.177+35C>A	intron	N/A	ENSP00000489123.1	A0A0U1RQQ9

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34121

AN:

151944

Hom.:

4321

Cov.:

show subpopulations

Gnomad AFR

AF:

0.326

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.191

Gnomad ASJ

AF:

0.208

Gnomad EAS

AF:

0.0408

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.172

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.222

GnomAD2 exomes

AF:

0.176

AC:

34725

AN:

197368

AF XY:

0.174

show subpopulations

Gnomad AFR exome

AF:

0.331

Gnomad AMR exome

AF:

0.128

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.0454

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.202

Gnomad OTH exome

AF:

0.181

GnomAD4 exome

AF:

0.196

AC:

270221

AN:

1378190

Hom.:

27985

Cov.:

AF XY:

0.194

AC XY:

132265

AN XY:

681926

show subpopulations

African (AFR)

AF:

0.327

AC:

9929

AN:

30348

American (AMR)

AF:

0.135

AC:

4369

AN:

32358

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

4372

AN:

22410

East Asian (EAS)

AF:

0.0455

AC:

1714

AN:

37678

South Asian (SAS)

AF:

0.119

AC:

8812

AN:

73972

European-Finnish (FIN)

AF:

0.138

AC:

7103

AN:

51608

Middle Eastern (MID)

AF:

0.174

AC:

938

AN:

5382

European-Non Finnish (NFE)

AF:

0.208

AC:

222112

AN:

1067628

Other (OTH)

AF:

0.191

AC:

10872

AN:

56806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

10069

20138

30208

40277

50346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7856

15712

23568

31424

39280

<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:

0.225

AC:

34188

AN:

152062

Hom.:

4337

Cov.:

AF XY:

0.218

AC XY:

16169

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.327

AC:

13539

AN:

41450

American (AMR)

AF:

0.191

AC:

2918

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.208

AC:

721

AN:

3466

East Asian (EAS)

AF:

0.0407

AC:

210

AN:

5156

South Asian (SAS)

AF:

0.115

AC:

551

AN:

4808

European-Finnish (FIN)

AF:

0.133

AC:

1412

AN:

10588

Middle Eastern (MID)

AF:

0.185

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.208

AC:

14119

AN:

68004

Other (OTH)

AF:

0.225

AC:

475

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1320

2640

3961

5281

6601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.208

Hom.:

5618

Bravo

AF:

0.234

Asia WGS

AF:

0.112

AC:

390

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.4

(source)

DANN

Benign

0.24

PhyloP100

1.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over