19-12767435-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_013312.3(HOOK2):c.1333G>C(p.Val445Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,614,010 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (46 hom.)
• Consequence: HOOK2 NM_013312.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.535

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027045012).
• BP6: Variant 19-12767435-C-G is Benign according to our data. Variant chr19-12767435-C-G is described in ClinVar as [Benign]. Clinvar id is 784829.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00409 (622/152212) while in subpopulation EAS AF= 0.0296 (153/5172). AF 95% confidence interval is 0.0258. There are 12 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOOK2	NM_013312.3	c.1333G>C	p.Val445Leu	missense_variant	14/23	ENST00000397668.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOOK2	ENST00000397668.8	c.1333G>C	p.Val445Leu	missense_variant	14/23	1	NM_013312.3	A1

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 617 AN: 152094 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00714 AC: 1782 AN: 249412 Hom.: 20 AF XY: 0.00576 AC XY: 779 AN XY: 135352

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.0281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0258

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.00462

GnomAD4 exome AF: 0.00218 AC: 3187 AN: 1461798 Hom.: 46 Cov.: 31 AF XY: 0.00199 AC XY: 1445 AN XY: 727212

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0261

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0270

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00272

GnomAD4 genome AF: 0.00409 AC: 622 AN: 152212 Hom.: 12 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74412

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0296

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.00980

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000107 Hom.: 1

Bravo AF: 0.00437

ExAC AF: 0.00562 AC: 679

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	11
Dann	Benign	0.36
DEOGEN2	Benign	0.0038	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.11	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.032
Sift	Benign	0.65	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.0010	B;B
Vest4		0.064
MutPred		0.56		Loss of glycosylation at T443 (P = 0.1449);Loss of glycosylation at T443 (P = 0.1449);
MVP		0.15
MPC		0.25
ClinPred		0.00012	T
GERP RS		1.0
Varity_R		0.020
gMVP		0.12

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: rs35979347; hg19: chr19-12878249;