20-20036212-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001278628.2(CRNKL1):c.2047G>A(p.Asp683Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D683A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: CRNKL1 NM_001278628.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13040605).
• BS2: High AC in GnomAd at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRNKL1	NM_001278628.2	c.2047G>A	p.Asp683Asn	missense_variant	14/14	ENST00000536226.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRNKL1	ENST00000536226.2	c.2047G>A	p.Asp683Asn	missense_variant	14/14	1	NM_001278628.2	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000307 AC: 77 AN: 250888 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135576

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000556

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000564 AC: 824 AN: 1461732 Hom.: 0 Cov.: 30 AF XY: 0.000524 AC XY: 381 AN XY: 727162

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000708

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74350

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000597 Hom.: 0

Bravo AF: 0.000438

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000545

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.2530G>A (p.D844N) alteration is located in exon 15 (coding exon 15) of the CRNKL1 gene. This alteration results from a G to A substitution at nucleotide position 2530, causing the aspartic acid (D) at amino acid position 844 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.017	T;T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.032	D;D;T
Sift4G	Uncertain	0.014	D;D;T
Polyphen		0.96	.;D;.
Vest4		0.12
MVP		0.40
MPC		0.27
ClinPred		0.052	T
GERP RS		5.1
Varity_R		0.049
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs148992156; hg19: chr20-20016856;