8-25184952-CG-GC

Variant names:

• chr8-25184953-T-C
• NM_024940.8:c.43+2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024940.8(DOCK5):​c.43+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOCK5 NM_024940.8 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 0 publications found

Genes affected

DOCK5 (HGNC:23476): (dedicator of cytokinesis 5) This gene encodes a member of the dedicator of cytokinesis protein family. Members of this family act as guanine nucleotide exchange factors for small Rho family G proteins. The protein encoded by this gene is thought to associate with adaptors CRK and CRKL, and function in regulation of intestinal epithelial cell spreading and migration on collagen IV. Similar proteins in mouse and zebrafish also function in myoblast fusion. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024940.8. 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
	DOCK5	NM_024940.8	MANE Select	c.43+2T>C		splice_donor intron	N/A	NP_079216.4
	DOCK5	NM_001322810.2		c.43+2T>C		splice_donor intron	N/A	NP_001309739.1	B9A015

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK5	ENST00000276440.12	TSL:1 MANE Select	c.43+2T>C		splice_donor intron	N/A	ENSP00000276440.7	Q9H7D0-1
	DOCK5	ENST00000481100.5	TSL:1	c.43+2T>C		splice_donor intron	N/A	ENSP00000429737.1	Q9H7D0-2
	DOCK5	ENST00000410074.5	TSL:2	c.43+2T>C		splice_donor intron	N/A	ENSP00000387036.1	B9A015

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1280154 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 631918

African (AFR) AF: 0.00 AC: 0 AN: 26784

American (AMR) AF: 0.00 AC: 0 AN: 24228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20100

East Asian (EAS) AF: 0.00 AC: 0 AN: 30730

South Asian (SAS) AF: 0.00 AC: 0 AN: 60936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1016152

Other (OTH) AF: 0.00 AC: 0 AN: 51106

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	30
DANN	Benign	0.92
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.33	N
PhyloP100		2.1
PromoterAI		-0.48	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-25042468;