20-20036229-T-C

Variant names:

• chr20-20036229-T-C
• NM_001278628.2:c.2030A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 3P and 8B. PM2 PP2 BP4_Strong BS2

The NM_001278628.2(CRNKL1):​c.2030A>G​(p.His677Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CRNKL1 NM_001278628.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

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

Our verdict: Likely_benign. 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).
• BP4: Computational evidence support a benign effect (MetaRNN=0.051451266).
• BS2: High AC in GnomAdExome4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRNKL1	NM_001278628.2	MANE Select	c.2030A>G	p.His677Arg	missense	Exon 14 of 14	NP_001265557.1	Q9BZJ0-2
	CRNKL1	NM_016652.6		c.2513A>G	p.His838Arg	missense	Exon 15 of 15	NP_057736.4
	CRNKL1	NM_001278625.2		c.2477A>G	p.His826Arg	missense	Exon 15 of 15	NP_001265554.1	Q5JY65

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRNKL1	ENST00000536226.2	TSL:1 MANE Select	c.2030A>G	p.His677Arg	missense	Exon 14 of 14	ENSP00000440733.1	Q9BZJ0-2
	CRNKL1	ENST00000377340.6	TSL:1	c.2513A>G	p.His838Arg	missense	Exon 15 of 15	ENSP00000366557.2	Q9BZJ0-1
	CRNKL1	ENST00000377327.8	TSL:1	c.2477A>G	p.His826Arg	missense	Exon 15 of 15	ENSP00000366544.4	Q5JY65

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461862 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.68
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.83
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.057
Sift	Benign	0.10	T
Sift4G	Benign	0.45	T
Polyphen		0.023	B
Vest4		0.13
MutPred		0.12		Gain of MoRF binding (P = 0.5143)
MVP		0.21
MPC		0.33
ClinPred		0.083	T
GERP RS		4.0
Varity_R		0.034
gMVP		0.21
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

hg19: chr20-20016873;