Genetic Variant NM_001278628.2:c.1653G>C (chr20-20037566-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2

The NM_001278628.2(CRNKL1):c.1653G>C(p.Trp551Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,610,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

CRNKL1
NM_001278628.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49

Publications

1 publications found

Variant links:

Genes affected

CRNKL1 (HGNC:15762): (crooked neck pre-mRNA splicing factor 1) The crooked neck (crn) gene of Drosophila is essential for embryogenesis and is thought to be involved in cell cycle progression and pre-mRNA splicing. A protein encoded by this human locus has been found to localize to pre-mRNA splicing complexes in the nucleus and is necessary for pre-mRNA splicing. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2013]

CRNKL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.87994 (below the threshold of 3.09). Trascript score misZ: 2.5211 (below the threshold of 3.09).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

BS2

High AC in GnomAdExome4 at 96 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278628.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRNKL1	NM_001278628.2	MANE Select	c.1653G>C	p.Trp551Cys	missense	Exon 13 of 14	NP_001265557.1	Q9BZJ0-2
CRNKL1	NM_016652.6		c.2136G>C	p.Trp712Cys	missense	Exon 14 of 15	NP_057736.4
CRNKL1	NM_001278625.2		c.2100G>C	p.Trp700Cys	missense	Exon 14 of 15	NP_001265554.1	Q5JY65

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRNKL1	ENST00000536226.2	TSL:1 MANE Select	c.1653G>C	p.Trp551Cys	missense	Exon 13 of 14	ENSP00000440733.1	Q9BZJ0-2
CRNKL1	ENST00000377340.6	TSL:1	c.2136G>C	p.Trp712Cys	missense	Exon 14 of 15	ENSP00000366557.2	Q9BZJ0-1
CRNKL1	ENST00000377327.8	TSL:1	c.2100G>C	p.Trp700Cys	missense	Exon 14 of 15	ENSP00000366544.4	Q5JY65

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000766

AC:

AN:

248172

AF XY:

0.0000595

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1458516

Hom.:

Cov.:

AF XY:

0.0000675

AC XY:

AN XY:

725496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33098

American (AMR)

AF:

0.00

AC:

AN:

43996

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26012

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

85476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000792

AC:

AN:

1111064

Other (OTH)

AF:

0.000116

AC:

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000676

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

3.8

PhyloP100

7.5

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-13

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.85

Loss of MoRF binding (P = 0.0214)

MVP

0.83

MPC

1.2

ClinPred

1.0

GERP RS

5.0

Varity_R

0.95

gMVP

0.86

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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