6-38866620-A-C

Variant names:

• chr6-38866620-A-C
• rs45532134
• NM_001206927.2:c.6528A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS1

The NM_001206927.2(DNAH8):​c.6528A>C​(p.Leu2176Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,612,280 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L2176L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580
• 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: 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.041).
• BP6: Variant 6-38866620-A-C is Benign according to our data. Variant chr6-38866620-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 414388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.058 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00112 (170/152330) while in subpopulation NFE AF = 0.00204 (139/68028). AF 95% confidence interval is 0.00177. There are 1 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.6528A>C	p.Leu2176Leu	synonymous_variant	Exon 46 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.6528A>C	p.Leu2176Leu	synonymous_variant	Exon 46 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.5877A>C	p.Leu1959Leu	synonymous_variant	Exon 44 of 91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.6528A>C	p.Leu2176Leu	synonymous_variant	Exon 45 of 82	5		ENSP00000415331.2
DNAH8	ENST00000394393.3	c.120A>C	p.Leu40Leu	synonymous_variant	Exon 2 of 4	3		ENSP00000377916.3

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00111 AC: 277 AN: 249970 AF XY: 0.00119

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000612

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.00200 AC: 2917 AN: 1459950 Hom.: 1 Cov.: 30 AF XY: 0.00191 AC XY: 1385 AN XY: 726064

African (AFR) AF: 0.000329 AC: 11 AN: 33428

American (AMR) AF: 0.000651 AC: 29 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39564

South Asian (SAS) AF: 0.000351 AC: 30 AN: 85446

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53380

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.00247 AC: 2741 AN: 1111420

Other (OTH) AF: 0.00121 AC: 73 AN: 60338

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74482

African (AFR) AF: 0.000361 AC: 15 AN: 41574

American (AMR) AF: 0.000784 AC: 12 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00204 AC: 139 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00114

Asia WGS AF: 0.000578 AC: 2 AN: 3472

EpiCase AF: 0.00208

EpiControl AF: 0.00243

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.9
DANN	Benign	0.80
PhyloP100		-0.058
Mutation Taster		=88/12	polymorphism

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: rs45532134; hg19: chr6-38834396;