rs117465420

Variant names:

• chr17-7831158-A-T
• rs117465420
• NM_020877.5:c.12303A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020877.5(DNAH2):​c.12303A>T​(p.Leu4101Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0235 in 1,614,068 control chromosomes in the GnomAD database, including 618 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (62 hom., cov: 32)
  • Exomes 𝑓: 0.024 (556 hom.)
• Consequence: DNAH2 NM_020877.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.05
• Publications: 11 publications found

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]

DNAH2 Gene-Disease associations (from GenCC):

• spermatogenic failure 45

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041172802).
• BP6: Variant 17-7831158-A-T is Benign according to our data. Variant chr17-7831158-A-T is described in ClinVar as Benign. ClinVar VariationId is 402715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH2	NM_020877.5	c.12303A>T	p.Leu4101Phe	missense_variant	Exon 80 of 86	ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6	c.12303A>T	p.Leu4101Phe	missense_variant	Exon 80 of 86	2	NM_020877.5	ENSP00000458355.1
DNAH2	ENST00000389173.6	c.12303A>T	p.Leu4101Phe	missense_variant	Exon 79 of 85	2		ENSP00000373825.2
DNAH2	ENST00000575105.1	c.3150A>T	p.Leu1050Phe	missense_variant	Exon 21 of 23	5		ENSP00000461726.1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3513 AN: 152102 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00727

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0514

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0245 AC: 6161 AN: 251444 AF XY: 0.0247

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0201

Gnomad ASJ exome AF: 0.0602

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0386

GnomAD4 exome AF: 0.0235 AC: 34421 AN: 1461848 Hom.: 556 Cov.: 32 AF XY: 0.0235 AC XY: 17121 AN XY: 727216

African (AFR) AF: 0.00541 AC: 181 AN: 33480

American (AMR) AF: 0.0221 AC: 990 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 1484 AN: 26134

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.00883 AC: 762 AN: 86258

European-Finnish (FIN) AF: 0.0496 AC: 2647 AN: 53380

Middle Eastern (MID) AF: 0.0848 AC: 489 AN: 5768

European-Non Finnish (NFE) AF: 0.0235 AC: 26093 AN: 1112010

Other (OTH) AF: 0.0293 AC: 1768 AN: 60394

GnomAD4 genome AF: 0.0231 AC: 3514 AN: 152220 Hom.: 62 Cov.: 32 AF XY: 0.0244 AC XY: 1815 AN XY: 74420

African (AFR) AF: 0.00727 AC: 302 AN: 41528

American (AMR) AF: 0.0346 AC: 530 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 205 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4822

European-Finnish (FIN) AF: 0.0514 AC: 544 AN: 10590

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0255 AC: 1733 AN: 68000

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0285 Hom.: 30

Bravo AF: 0.0212

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0295 AC: 254

ExAC AF: 0.0232 AC: 2816

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0345

EpiControl AF: 0.0338

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNAH2-related disorder Benign:1

May 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	0.090
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	.;T;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		4.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	.;N;.
REVEL	Benign	0.083
Sift	Benign	0.050	.;D;.
Sift4G	Uncertain	0.055	.;.;T
Polyphen		0.41	B;B;.
Vest4		0.097
MutPred		0.34		Loss of ubiquitination at K4096 (P = 0.0992);Loss of ubiquitination at K4096 (P = 0.0992);.;
MPC		0.50
ClinPred		0.019	T
GERP RS		3.6
Varity_R		0.40
gMVP		0.14
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117465420; hg19: chr17-7734476; COSMIC: COSV66728303;