chr17-7734248-C-T

Position:

• chr17-7734248-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020877.5(DNAH2):​c.694C>T​(p.Pro232Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: 2.24

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 1 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=0.19755211).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH2	NM_020877.5	c.694C>T	p.Pro232Ser	missense_variant	6/86	ENST00000572933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH2	ENST00000572933.6	c.694C>T	p.Pro232Ser	missense_variant	6/86	2	NM_020877.5	P1
DNAH2	ENST00000570791.5	c.694C>T	p.Pro232Ser	missense_variant	6/14	1
DNAH2	ENST00000389173.6	c.694C>T	p.Pro232Ser	missense_variant	5/85	2		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.694C>T (p.P232S) alteration is located in exon 5 (coding exon 5) of the DNAH2 gene. This alteration results from a C to T substitution at nucleotide position 694, causing the proline (P) at amino acid position 232 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	.;.;N
REVEL	Benign	0.12
Sift	Benign	0.17	.;.;T
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		0.67	P;D;P
Vest4		0.33
MutPred		0.33		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.40
MPC		0.26
ClinPred		0.47	T
GERP RS		5.4
Varity_R		0.059
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7637566;