19-12763685-G-A

Variant names:

• chr19-12763685-G-A
• rs368995729
• NM_013312.3:c.1921C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_013312.3(HOOK2):​c.1921C>T​(p.Arg641Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,072 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R641H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (2 hom.)
• Consequence: HOOK2 NM_013312.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33476663).
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1921C>T	p.Arg641Cys	missense	Exon 21 of 23	NP_037444.2	Q96ED9-1
	HOOK2	NM_001400041.1		c.2023C>T	p.Arg675Cys	missense	Exon 20 of 22	NP_001386970.1
	HOOK2	NM_001100176.2		c.1915C>T	p.Arg639Cys	missense	Exon 20 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.1921C>T	p.Arg641Cys	missense	Exon 21 of 23	ENSP00000380785.2	Q96ED9-1
	HOOK2	ENST00000264827.9	TSL:1	c.1915C>T	p.Arg639Cys	missense	Exon 20 of 22	ENSP00000264827.4	Q96ED9-2
	HOOK2	ENST00000894580.1		c.2209C>T	p.Arg737Cys	missense	Exon 20 of 22	ENSP00000564639.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152232 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: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 30 AN: 250246 AF XY: 0.000140

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461840 Hom.: 2 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727230

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.000614 AC: 53 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111966

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.13
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.63		Loss of MoRF binding (P = 0.0121)
MVP		0.38
MPC		0.86
ClinPred		0.52	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.29
Mutation Taster		=88/12	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: rs368995729; hg19: chr19-12874499;