19-12763569-C-T

Variant names:

• chr19-12763569-C-T
• rs189241336
• NM_013312.3:c.1969G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_013312.3(HOOK2):​c.1969G>A​(p.Glu657Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00868 in 1,614,220 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (77 hom.)
• Consequence: HOOK2 NM_013312.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.11
• Publications: 17 publications found

Genes affected

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008423775).
• BP6: Variant 19-12763569-C-T is Benign according to our data. Variant chr19-12763569-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 774525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013312.3. 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
	HOOK2	NM_013312.3	MANE Select	c.1969G>A	p.Glu657Lys	missense	Exon 22 of 23	NP_037444.2	Q96ED9-1
	HOOK2	NM_001400041.1		c.2071G>A	p.Glu691Lys	missense	Exon 21 of 22	NP_001386970.1
	HOOK2	NM_001100176.2		c.1963G>A	p.Glu655Lys	missense	Exon 21 of 22	NP_001093646.1	Q96ED9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOOK2	ENST00000397668.8	TSL:1 MANE Select	c.1969G>A	p.Glu657Lys	missense	Exon 22 of 23	ENSP00000380785.2	Q96ED9-1
	HOOK2	ENST00000264827.9	TSL:1	c.1963G>A	p.Glu655Lys	missense	Exon 21 of 22	ENSP00000264827.4	Q96ED9-2
	HOOK2	ENST00000894580.1		c.2257G>A	p.Glu753Lys	missense	Exon 21 of 22	ENSP00000564639.1

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 857 AN: 152214 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00671

GnomAD2 exomes AF: 0.00559 AC: 1402 AN: 250890 AF XY: 0.00554

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00955

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00900 AC: 13154 AN: 1461888 Hom.: 77 Cov.: 33 AF XY: 0.00864 AC XY: 6284 AN XY: 727246

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00239 AC: 107 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00327 AC: 282 AN: 86258

European-Finnish (FIN) AF: 0.00243 AC: 130 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0108 AC: 12039 AN: 1112008

Other (OTH) AF: 0.00816 AC: 493 AN: 60396

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152332 Hom.: 3 Cov.: 32 AF XY: 0.00487 AC XY: 363 AN XY: 74486

African (AFR) AF: 0.00135 AC: 56 AN: 41578

American (AMR) AF: 0.00386 AC: 59 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0101 AC: 684 AN: 68034

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00834 Hom.: 20

Bravo AF: 0.00545

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00544 AC: 660

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00845

EpiControl AF: 0.0100

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		0.98	D
Vest4		0.50
MVP		0.28
MPC		0.93
ClinPred		0.040	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.32
Mutation Taster		=91/9	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

dbSNP: rs189241336; hg19: chr19-12874383; COSMIC: COSV99063161; COSMIC: COSV99063161;