rs1060499854

Positions:

• chr17-7771420-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_020877.5(DNAH2):​c.4453G>C​(p.Asp1485His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNAH2 NM_020877.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNAH2. . Gene score misZ 1.883 (greater than the threshold 3.09). Trascript score misZ 4.8003 (greater than threshold 3.09). GenCC has associacion of gene with spermatogenic failure 45.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38704646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH2	NM_020877.5	c.4453G>C	p.Asp1485His	missense_variant	28/86	ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6	c.4453G>C	p.Asp1485His	missense_variant	28/86	2	NM_020877.5	ENSP00000458355.1
DNAH2	ENST00000389173.6	c.4453G>C	p.Asp1485His	missense_variant	27/85	2		ENSP00000373825.2
DNAH2	ENST00000574518.1	n.*829G>C		non_coding_transcript_exon_variant	9/22	2		ENSP00000461273.1
DNAH2	ENST00000574518.1	n.*829G>C		3_prime_UTR_variant	9/22	2		ENSP00000461273.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, 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: Candidate PCD gene - no second variant and not really consistent with patient phenotype. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.081
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.064
Sift	Benign	0.11	.;T
Polyphen		0.26	B;B
Vest4		0.46
MutPred		0.37		Loss of ubiquitination at K1489 (P = 0.0329);Loss of ubiquitination at K1489 (P = 0.0329);
MVP		0.47
MPC		0.80
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.40
gMVP		0.43

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: rs1060499854; hg19: chr17-7674738;