rs116888435

Variant names:

• chr11-103120787-A-G
• rs116888435
• NM_001080463.2:c.1233A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001377.3(DYNC2H1):​c.1233A>G​(p.Gln411Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,561,178 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 32)
  • Exomes 𝑓: 0.017 (232 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.352
• Publications: 4 publications found

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, ClinGen
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 11-103120787-A-G is Benign according to our data. Variant chr11-103120787-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.352 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0142 (2160/152092) while in subpopulation AMR AF = 0.0225 (343/15272). AF 95% confidence interval is 0.0205. There are 26 homozygotes in GnomAd4. There are 1019 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377.3. 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
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.1233A>G	p.Gln411Gln	synonymous	Exon 8 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.1233A>G	p.Gln411Gln	synonymous	Exon 8 of 89	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.1233A>G	p.Gln411Gln	synonymous	Exon 8 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.1233A>G	p.Gln411Gln	synonymous	Exon 8 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.1233A>G	p.Gln411Gln	synonymous	Exon 8 of 20	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2164 AN: 151976 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00961

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0160 AC: 2760 AN: 172070 AF XY: 0.0161

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0434

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0167 AC: 23592 AN: 1409086 Hom.: 232 Cov.: 31 AF XY: 0.0169 AC XY: 11770 AN XY: 697192

African (AFR) AF: 0.00343 AC: 110 AN: 32072

American (AMR) AF: 0.0139 AC: 513 AN: 36812

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 1030 AN: 25280

East Asian (EAS) AF: 0.00 AC: 0 AN: 37020

South Asian (SAS) AF: 0.0125 AC: 1011 AN: 80936

European-Finnish (FIN) AF: 0.00942 AC: 463 AN: 49172

Middle Eastern (MID) AF: 0.0372 AC: 186 AN: 4994

European-Non Finnish (NFE) AF: 0.0177 AC: 19202 AN: 1084534

Other (OTH) AF: 0.0185 AC: 1077 AN: 58266

GnomAD4 genome AF: 0.0142 AC: 2160 AN: 152092 Hom.: 26 Cov.: 32 AF XY: 0.0137 AC XY: 1019 AN XY: 74376

African (AFR) AF: 0.00337 AC: 140 AN: 41542

American (AMR) AF: 0.0225 AC: 343 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4830

European-Finnish (FIN) AF: 0.00961 AC: 101 AN: 10510

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0194 AC: 1320 AN: 67964

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0195 Hom.: 34

Bravo AF: 0.0148

Asia WGS AF: 0.00810 AC: 28 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	2	not provided (2)
-	-	1	Jeune thoracic dystrophy (1)
-	-	1	Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.7
DANN	Benign	0.53
PhyloP100		0.35
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116888435; hg19: chr11-102991516;