chr20-32074623-A-G

Variant names:

• chr20-32074623-A-G
• rs140850435
• NM_002110.5:c.330A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002110.5(HCK):​c.330A>G​(p.Glu110Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,608,494 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: HCK NM_002110.5 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.69
• Publications: 0 publications found

Genes affected

HCK (HGNC:4840): (HCK proto-oncogene, Src family tyrosine kinase) The protein encoded by this gene is a member of the Src family of tyrosine kinases. This protein is primarily hemopoietic, particularly in cells of the myeloid and B-lymphoid lineages. It may help couple the Fc receptor to the activation of the respiratory burst. In addition, it may play a role in neutrophil migration and in the degranulation of neutrophils. Multiple isoforms with different subcellular distributions are produced due to both alternative splicing and the use of alternative translation initiation codons, including a non-AUG (CUG) codon. [provided by RefSeq, Feb 2010]

HCK Gene-Disease associations (from GenCC):

• autoinflammation with pulmonary and cutaneous vasculitis

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 20-32074623-A-G is Benign according to our data. Variant chr20-32074623-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3770454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.69 with no splicing effect.
• BS2: High AC in GnomAd4 at 222 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002110.5. 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
	HCK	NM_002110.5	MANE Select	c.330A>G	p.Glu110Glu	splice_region synonymous	Exon 5 of 13	NP_002101.2
	HCK	NM_001172130.3		c.327A>G	p.Glu109Glu	splice_region synonymous	Exon 5 of 13	NP_001165601.1	P08631-4
	HCK	NM_001172132.3		c.270A>G	p.Glu90Glu	splice_region synonymous	Exon 6 of 14	NP_001165603.1	A8K4G3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCK	ENST00000375852.5	TSL:1 MANE Select	c.330A>G	p.Glu110Glu	splice_region synonymous	Exon 5 of 13	ENSP00000365012.3	P08631-1
	HCK	ENST00000375862.7	TSL:1	c.327A>G	p.Glu109Glu	splice_region synonymous	Exon 5 of 13	ENSP00000365022.3	P08631-4
	HCK	ENST00000520553.5	TSL:1	c.267A>G	p.Glu89Glu	splice_region synonymous	Exon 5 of 13	ENSP00000429848.1	P08631-2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152070 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00996

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00196 AC: 493 AN: 251328 AF XY: 0.00239

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00163 AC: 2369 AN: 1456306 Hom.: 10 Cov.: 29 AF XY: 0.00186 AC XY: 1348 AN XY: 724898

African (AFR) AF: 0.000210 AC: 7 AN: 33350

American (AMR) AF: 0.00134 AC: 60 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 87 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00743 AC: 640 AN: 86162

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53406

Middle Eastern (MID) AF: 0.00400 AC: 23 AN: 5756

European-Non Finnish (NFE) AF: 0.00131 AC: 1445 AN: 1106946

Other (OTH) AF: 0.00163 AC: 98 AN: 60210

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152188 Hom.: 1 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74404

African (AFR) AF: 0.000145 AC: 6 AN: 41518

American (AMR) AF: 0.00203 AC: 31 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68000

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.00127

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		2.7
Mutation Taster		=44/56	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: rs140850435; hg19: chr20-30662426; COSMIC: COSV105870381; COSMIC: COSV105870381;