17-7770610-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020877.5(DNAH2):c.4152C>G(p.Pro1384=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,714 control chromosomes in the GnomAD database, including 67,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7181 hom., cov: 31)
  • Exomes 𝑓: 0.28 (60263 hom.)
• Consequence: DNAH2 NM_020877.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.31

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 17-7770610-C-G is Benign according to our data. Variant chr17-7770610-C-G is described in ClinVar as [Benign]. Clinvar id is 402707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH2	NM_020877.5	c.4152C>G	p.Pro1384=	synonymous_variant	26/86	ENST00000572933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH2	ENST00000572933.6	c.4152C>G	p.Pro1384=	synonymous_variant	26/86	2	NM_020877.5	P1
DNAH2	ENST00000389173.6	c.4152C>G	p.Pro1384=	synonymous_variant	25/85	2		P1
DNAH2	ENST00000574518.1	c.*415C>G		3_prime_UTR_variant, NMD_transcript_variant	8/22	2

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45947 AN: 151938 Hom.: 7174 Cov.: 31

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.292

GnomAD3 exomes AF: 0.324 AC: 81394 AN: 251408 Hom.: 14106 AF XY: 0.319 AC XY: 43318 AN XY: 135884

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.492

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.408

Gnomad SAS exome AF: 0.365

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.294

GnomAD4 exome AF: 0.282 AC: 411700 AN: 1461658 Hom.: 60263 Cov.: 37 AF XY: 0.283 AC XY: 205594 AN XY: 727134

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.482

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.387

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.292

GnomAD4 genome AF: 0.302 AC: 45997 AN: 152056 Hom.: 7181 Cov.: 31 AF XY: 0.309 AC XY: 22978 AN XY: 74348

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.369

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.293

Alfa AF: 0.230 Hom.: 1339

Bravo AF: 0.310

Asia WGS AF: 0.391 AC: 1357 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.252

ClinVar

Significance: Benign

Submissions summary: Benign:2

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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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
BayesDel_noAF	Benign	-0.34
Cadd	Benign	9.3
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9909288; hg19: chr17-7673928; COSMIC: COSV66716508;