Genetic Variant NM_001278628.2:c.1232T>C (chr20-20040759-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001278628.2(CRNKL1):c.1232T>C(p.Phe411Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F411C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CRNKL1
NM_001278628.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.10

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.918

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.1232T>C	p.Phe411Ser	missense	Exon 10 of 14	NP_001265557.1	Q9BZJ0-2
CRNKL1	NM_016652.6		c.1715T>C	p.Phe572Ser	missense	Exon 11 of 15	NP_057736.4
CRNKL1	NM_001278625.2		c.1679T>C	p.Phe560Ser	missense	Exon 11 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.1232T>C	p.Phe411Ser	missense	Exon 10 of 14	ENSP00000440733.1	Q9BZJ0-2
CRNKL1	ENST00000377340.6	TSL:1	c.1715T>C	p.Phe572Ser	missense	Exon 11 of 15	ENSP00000366557.2	Q9BZJ0-1
CRNKL1	ENST00000377327.8	TSL:1	c.1679T>C	p.Phe560Ser	missense	Exon 11 of 15	ENSP00000366544.4	Q5JY65

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454498

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33316

American (AMR)

AF:

0.00

AC:

AN:

44058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.00

AC:

AN:

84402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109482

Other (OTH)

AF:

0.00

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.8

PhyloP100

9.1

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.5

REVEL

Uncertain

0.54

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Polyphen

0.86

Vest4

0.88

MutPred

0.80

Gain of disorder (P = 0.038)

MVP

0.66

MPC

1.3

ClinPred

0.99

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.87

Mutation Taster

=36/64

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over