NM_001206927.2:c.1764+2T>C

Variant names:

• chr6-38770561-T-C
• rs77769111
• NM_001206927.2:c.1764+2T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_001206927.2(DNAH8):​c.1764+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00394 in 1,595,600 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (123 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (75 hom.)
• Consequence: DNAH8 NM_001206927.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9947
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.03
• Publications: 5 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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: Benign. The variant received -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.010407817 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 6-38770561-T-C is Benign according to our data. Variant chr6-38770561-T-C is described in ClinVar as Benign. ClinVar VariationId is 414428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.1764+2T>C		splice_donor intron	N/A	NP_001193856.1
	DNAH8	NM_001371.4		c.1113+2T>C		splice_donor intron	N/A	NP_001362.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.1764+2T>C		splice_donor intron	N/A	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.1113+2T>C		splice_donor intron	N/A	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.1764+2T>C		splice_donor intron	N/A	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3237 AN: 152156 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.00570 AC: 1317 AN: 231170 AF XY: 0.00411

Gnomad AFR exome AF: 0.0695

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.000229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.00211 AC: 3042 AN: 1443326 Hom.: 75 Cov.: 30 AF XY: 0.00187 AC XY: 1340 AN XY: 717530

African (AFR) AF: 0.0708 AC: 2291 AN: 32380

American (AMR) AF: 0.00522 AC: 210 AN: 40218

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.0000732 AC: 6 AN: 81978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52764

Middle Eastern (MID) AF: 0.00547 AC: 31 AN: 5670

European-Non Finnish (NFE) AF: 0.000201 AC: 222 AN: 1106156

Other (OTH) AF: 0.00472 AC: 281 AN: 59544

GnomAD4 genome AF: 0.0213 AC: 3250 AN: 152274 Hom.: 123 Cov.: 32 AF XY: 0.0207 AC XY: 1543 AN XY: 74468

African (AFR) AF: 0.0735 AC: 3052 AN: 41544

American (AMR) AF: 0.00882 AC: 135 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68010

Other (OTH) AF: 0.0147 AC: 31 AN: 2108

Alfa AF: 0.00814 Hom.: 70

Bravo AF: 0.0234

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0647 AC: 285

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00666 AC: 809

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.0
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=59/41	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs77769111; hg19: chr6-38738337;