chr17-1455914-G-C

Position:

• chr17-1455914-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016823.4(CRK):​c.204C>G​(p.Arg68Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,583,352 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (21 hom.)
• Consequence: CRK NM_016823.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.536

Genes affected

CRK (HGNC:2362): (CRK proto-oncogene, adaptor protein) This gene encodes a member of an adapter protein family that binds to several tyrosine-phosphorylated proteins. The product of this gene has several SH2 and SH3 domains (src-homology domains) and is involved in several signaling pathways, recruiting cytoplasmic proteins in the vicinity of tyrosine kinase through SH2-phosphotyrosine interaction. The N-terminal SH2 domain of this protein functions as a positive regulator of transformation whereas the C-terminal SH3 domain functions as a negative regulator of transformation. Two alternative transcripts encoding different isoforms with distinct biological activity have been described. [provided by RefSeq, Jul 2008]

CRK (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 17-1455914-G-C is Benign according to our data. Variant chr17-1455914-G-C is described in ClinVar as [Benign]. Clinvar id is 768814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.536 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1630/152160) while in subpopulation AFR AF= 0.0371 (1541/41536). AF 95% confidence interval is 0.0356. There are 39 homozygotes in gnomad4. There are 758 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1630 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRK	NM_016823.4	c.204C>G	p.Arg68Arg	synonymous_variant	1/3	ENST00000300574.3	NP_058431.2
CRK	NM_005206.5	c.204C>G	p.Arg68Arg	synonymous_variant	1/3		NP_005197.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRK	ENST00000300574.3	c.204C>G	p.Arg68Arg	synonymous_variant	1/3	1	NM_016823.4	ENSP00000300574.2
CRK	ENST00000398970.5	c.204C>G	p.Arg68Arg	synonymous_variant	1/3	1		ENSP00000381942.5
CRK	ENST00000574295.1	c.204C>G	p.Arg68Arg	synonymous_variant	1/3	5		ENSP00000459505.1
CRK	ENST00000572145.1	n.210+7039C>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1624 AN: 152052 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00241 AC: 485 AN: 201662 Hom.: 7 AF XY: 0.00169 AC XY: 191 AN XY: 113024

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000291

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00102 AC: 1457 AN: 1431192 Hom.: 21 Cov.: 30 AF XY: 0.000830 AC XY: 591 AN XY: 711710

Gnomad4 AFR exome AF: 0.0350

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000203

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.00251

GnomAD4 genome AF: 0.0107 AC: 1630 AN: 152160 Hom.: 39 Cov.: 32 AF XY: 0.0102 AC XY: 758 AN XY: 74386

Gnomad4 AFR AF: 0.0371

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.0117

Asia WGS AF: 0.00145 AC: 5 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.88

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: rs61762263; hg19: chr17-1359208;