rs872346

Positions:

• chr17-7817712-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020877.5(DNAH2):​c.10169+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,613,956 control chromosomes in the GnomAD database, including 103,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6908 hom., cov: 31)
  • Exomes 𝑓: 0.35 (96143 hom.)
• Consequence: DNAH2 NM_020877.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002793
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.05

Genes affected

DNAH2 (HGNC:2948): (dynein axonemal heavy chain 2) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. The axonemal dyneins, found in cilia and flagella, are components of the outer and inner dynein arms attached to the peripheral microtubule doublets. DNAH2 is an axonemal inner arm dynein heavy chain (Chapelin et al., 1997 [PubMed 9256245]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-7817712-G-A is Benign according to our data. Variant chr17-7817712-G-A is described in ClinVar as [Benign]. Clinvar id is 402712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH2	NM_020877.5	c.10169+3G>A		splice_region_variant, intron_variant		ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6	c.10169+3G>A		splice_region_variant, intron_variant		2	NM_020877.5	ENSP00000458355.1
DNAH2	ENST00000389173.6	c.10169+3G>A		splice_region_variant, intron_variant		2		ENSP00000373825.2
DNAH2	ENST00000575105.1	c.1016+3G>A		splice_region_variant, intron_variant		5		ENSP00000461726.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42068 AN: 151970 Hom.: 6902 Cov.: 31

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.280 AC: 70247 AN: 251192 Hom.: 11693 AF XY: 0.286 AC XY: 38832 AN XY: 135772

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.0626

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.286

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.351 AC: 512761 AN: 1461866 Hom.: 96143 Cov.: 86 AF XY: 0.347 AC XY: 252292 AN XY: 727228

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.0681

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.331

GnomAD4 genome AF: 0.277 AC: 42107 AN: 152090 Hom.: 6908 Cov.: 31 AF XY: 0.268 AC XY: 19939 AN XY: 74346

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.0639

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.310

Alfa AF: 0.366 Hom.: 17756

Bravo AF: 0.269

Asia WGS AF: 0.124 AC: 430 AN: 3478

EpiCase AF: 0.409

EpiControl AF: 0.401

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

DNAH2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.082
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.036
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: rs872346; hg19: chr17-7721030; COSMIC: COSV66719233;