rs2278426

chr19-11239812-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018687.7(ANGPTL8):c.175C>T(p.Arg59Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,604,966 control chromosomes in the GnomAD database, including 6,838 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1237 hom., cov: 32)
  • Exomes 𝑓: 0.062 (5601 hom.)
• Consequence: ANGPTL8 NM_018687.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.623

Genes affected

ANGPTL8 (HGNC:24933): (angiopoietin like 8) Predicted to enable hormone activity. Involved in regulation of lipid metabolic process and triglyceride homeostasis. Acts upstream of or within positive regulation of protein processing and regulation of lipoprotein metabolic process. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

DOCK6 (HGNC:19189): (dedicator of cytokinesis 6) This gene encodes a member of the dedicator of cytokinesis (DOCK) family of atypical guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with small GTPases and are components of intracellular signaling networks. The encoded protein is a group C DOCK protein and plays a role in actin cytoskeletal reorganization by activating the Rho GTPases Cdc42 and Rac1. Mutations in this gene are associated with Adams-Oliver syndrome 2. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037017763).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL8	NM_018687.7	c.175C>T	p.Arg59Trp	missense_variant	1/4	ENST00000252453.12
DOCK6	NM_020812.4	c.1644-1508G>A		intron_variant		ENST00000294618.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL8	ENST00000252453.12	c.175C>T	p.Arg59Trp	missense_variant	1/4	1	NM_018687.7	P1
DOCK6	ENST00000294618.12	c.1644-1508G>A		intron_variant		1	NM_020812.4	A2
ANGPTL8	ENST00000591200.5	c.1-323C>T		intron_variant		1
DOCK6	ENST00000587656.6	c.1644-1508G>A		intron_variant		5		P3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16151 AN: 152050 Hom.: 1239 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0432

Gnomad OTH AF: 0.0952

GnomAD3 exomes AF: 0.113 AC: 25993 AN: 230988 Hom.: 2454 AF XY: 0.105 AC XY: 13241 AN XY: 125560

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.258

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.0650

Gnomad NFE exome AF: 0.0432

Gnomad OTH exome AF: 0.0805

GnomAD4 exome AF: 0.0622 AC: 90311 AN: 1452798 Hom.: 5601 Cov.: 32 AF XY: 0.0641 AC XY: 46277 AN XY: 722036

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.0217

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.0650

Gnomad4 NFE exome AF: 0.0378

Gnomad4 OTH exome AF: 0.0708

GnomAD4 genome AF: 0.106 AC: 16177 AN: 152168 Hom.: 1237 Cov.: 32 AF XY: 0.112 AC XY: 8364 AN XY: 74390

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.252

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.0644

Gnomad4 NFE AF: 0.0433

Gnomad4 OTH AF: 0.0942

Alfa AF: 0.0563 Hom.: 630

Bravo AF: 0.120

TwinsUK AF: 0.0405 AC: 150

ALSPAC AF: 0.0363 AC: 140

ESP6500AA AF: 0.171 AC: 673

ESP6500EA AF: 0.0482 AC: 399

ExAC AF: 0.104 AC: 12541

Asia WGS AF: 0.163 AC: 570 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.77	T;.
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.12
MPC		0.70
ClinPred		0.030	T
GERP RS		3.5
Varity_R		0.31
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs2278426; hg19: chr19-11350488; COSMIC: COSV99370870; COSMIC: COSV99370870;