NM_001278628.2:c.1604G>A

Variant names:

• chr20-20038392-C-T
• rs200745538
• NM_001278628.2:c.1604G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001278628.2(CRNKL1):​c.1604G>A​(p.Arg535Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,552,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: CRNKL1 NM_001278628.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71
• Publications: 1 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.

• 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=0.09726122).
• BS2: High AC in GnomAd4 at 15 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.1604G>A	p.Arg535Gln	missense	Exon 12 of 14	NP_001265557.1	Q9BZJ0-2
	CRNKL1	NM_016652.6		c.2087G>A	p.Arg696Gln	missense	Exon 13 of 15	NP_057736.4
	CRNKL1	NM_001278625.2		c.2051G>A	p.Arg684Gln	missense	Exon 13 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.1604G>A	p.Arg535Gln	missense	Exon 12 of 14	ENSP00000440733.1	Q9BZJ0-2
	CRNKL1	ENST00000377340.6	TSL:1	c.2087G>A	p.Arg696Gln	missense	Exon 13 of 15	ENSP00000366557.2	Q9BZJ0-1
	CRNKL1	ENST00000377327.8	TSL:1	c.2051G>A	p.Arg684Gln	missense	Exon 13 of 15	ENSP00000366544.4	Q5JY65

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000138 AC: 22 AN: 159178 AF XY: 0.000108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000447

GnomAD4 exome AF: 0.0000636 AC: 89 AN: 1400404 Hom.: 0 Cov.: 30 AF XY: 0.0000594 AC XY: 41 AN XY: 690802

African (AFR) AF: 0.00 AC: 0 AN: 31652

American (AMR) AF: 0.00 AC: 0 AN: 35908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25272

East Asian (EAS) AF: 0.00195 AC: 70 AN: 35902

South Asian (SAS) AF: 0.00 AC: 0 AN: 79348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000158 AC: 17 AN: 1079238

Other (OTH) AF: 0.0000345 AC: 2 AN: 58038

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74424

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000100 AC: 10

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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	0.33
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.097	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.78
MPC		0.62
ClinPred		0.66	D
GERP RS		5.8
Varity_R		0.79
gMVP		0.78
Mutation Taster		=22/78	disease causing

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

dbSNP: rs200745538; hg19: chr20-20019036;