6-39867814-G-C

Variant summary

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

The NM_001201427.2(DAAM2):c.733G>C(p.Val245Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,607,924 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (9 hom.)
• Consequence: DAAM2 NM_001201427.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.09

Genes affected

DAAM2 (HGNC:18143): (dishevelled associated activator of morphogenesis 2) Predicted to enable actin binding activity and small GTPase binding activity. Predicted to be involved in nervous system development and regulation of Wnt signaling pathway. Predicted to act upstream of or within determination of left/right symmetry. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009631813).
• BP6: Variant 6-39867814-G-C is Benign according to our data. Variant chr6-39867814-G-C is described in ClinVar as [Benign]. Clinvar id is 3038169.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00596 (908/152368) while in subpopulation AFR AF= 0.0203 (843/41586). AF 95% confidence interval is 0.0191. There are 6 homozygotes in gnomad4. There are 424 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAAM2	NM_001201427.2	c.733G>C	p.Val245Leu	missense_variant	6/25	ENST00000274867.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAAM2	ENST00000274867.9	c.733G>C	p.Val245Leu	missense_variant	6/25	1	NM_001201427.2	P1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 905 AN: 152250 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00171 AC: 399 AN: 233810 Hom.: 2 AF XY: 0.00127 AC XY: 162 AN XY: 127230

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000618 AC: 899 AN: 1455556 Hom.: 9 Cov.: 30 AF XY: 0.000560 AC XY: 405 AN XY: 723556

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000818

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00596 AC: 908 AN: 152368 Hom.: 6 Cov.: 33 AF XY: 0.00569 AC XY: 424 AN XY: 74516

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00719

ESP6500AA AF: 0.0210 AC: 92

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00202 AC: 245

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DAAM2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.038	T;T;.;T
Eigen	Benign	-0.066
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;.;D;D
MetaRNN	Benign	0.0096	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.017	.;B;.;B
Vest4		0.24
MutPred		0.50		Loss of phosphorylation at Y246 (P = 0.1599);Loss of phosphorylation at Y246 (P = 0.1599);Loss of phosphorylation at Y246 (P = 0.1599);Loss of phosphorylation at Y246 (P = 0.1599);
MVP		0.49
MPC		0.18
ClinPred		0.014	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.42

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: rs114233535; hg19: chr6-39835590; COSMIC: COSV99075378; COSMIC: COSV99075378;