NM_001206927.2:c.7281C>G

Variant names:

• chr6-38872949-C-G
• rs544209258
• NM_001206927.2:c.7281C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001206927.2(DNAH8):​c.7281C>G​(p.Ile2427Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I2427I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 0 publications found

Genes affected

DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

DNAH8 Gene-Disease associations (from GenCC):

• spermatogenic failure 46

  Inheritance: AR Classification: STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• spermatogenic failure 5

  Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.7281C>G	p.Ile2427Met	missense	Exon 51 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.6630C>G	p.Ile2210Met	missense	Exon 50 of 92	NP_001362.2	Q96JB1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.7281C>G	p.Ile2427Met	missense	Exon 51 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.6630C>G	p.Ile2210Met	missense	Exon 49 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.7281C>G	p.Ile2427Met	missense	Exon 50 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.078
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.58		Loss of catalytic residue at L2215 (P = 0.0285)
MVP		0.61
MPC		0.58
ClinPred		0.99	D
GERP RS		0.72
Varity_R		0.63
gMVP		0.53
Mutation Taster		=50/50

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: rs544209258; hg19: chr6-38840725;