rs869312924

Variant names:

• chr11-103154606-G-A
• rs869312924
• NM_001080463.2:c.3458G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001377.3(DYNC2H1):​c.3458G>A​(p.Arg1153Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000944 in 1,588,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1153W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.94
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.3458G>A	p.Arg1153Gln	missense splice_region	Exon 23 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.3458G>A	p.Arg1153Gln	missense splice_region	Exon 23 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.3458G>A	p.Arg1153Gln	missense splice_region	Exon 23 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.3458G>A	p.Arg1153Gln	missense splice_region	Exon 23 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+20187G>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151836 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000466 AC: 1 AN: 214384 AF XY: 0.00000866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000974 AC: 14 AN: 1436872 Hom.: 0 Cov.: 31 AF XY: 0.00000842 AC XY: 6 AN XY: 712874

African (AFR) AF: 0.00 AC: 0 AN: 32392

American (AMR) AF: 0.0000254 AC: 1 AN: 39444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25476

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80436

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000998 AC: 11 AN: 1102196

Other (OTH) AF: 0.00 AC: 0 AN: 59382

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151836 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74164

African (AFR) AF: 0.0000242 AC: 1 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15226

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67892

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Asphyxiating thoracic dystrophy 3 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Jeune thoracic dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.81		Loss of ubiquitination at K1155 (P = 0.0863)
MVP		0.74
MPC		0.36
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.46
gMVP		0.57
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.79		Position offset: 0

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

Other links and lift over

dbSNP: rs869312924; hg19: chr11-103025335;