NM_001080463.2:c.4267C>T

Variant names:

• chr11-103158916-C-T
• rs745870321
• NM_001080463.2:c.4267C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001080463.2(DYNC2H1):​c.4267C>T​(p.Arg1423Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,452,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1423H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.56
• 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), G2P, Orphanet, Ambry Genetics
• 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: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-103158917-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2573452.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 11-103158916-C-T is Pathogenic according to our data. Variant chr11-103158916-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. 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
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.4267C>T	p.Arg1423Cys	missense	Exon 28 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.4267C>T	p.Arg1423Cys	missense	Exon 28 of 89	NP_001368.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.4267C>T	p.Arg1423Cys	missense	Exon 28 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.4267C>T	p.Arg1423Cys	missense	Exon 28 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+24497C>T		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000291 AC: 7 AN: 240168 AF XY: 0.0000385

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000172

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1452986 Hom.: 0 Cov.: 31 AF XY: 0.0000194 AC XY: 14 AN XY: 721730

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.0000230 AC: 1 AN: 43512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39498

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1109060

Other (OTH) AF: 0.0000166 AC: 1 AN: 60142

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000610 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Asphyxiating thoracic dystrophy 3 (6)
1	-	-	Jeune thoracic dystrophy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.90		Loss of disorder (P = 0.0222)
MVP		0.87
MPC		0.44
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.88
gMVP		0.87
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs745870321; hg19: chr11-103029645; COSMIC: COSV62095418;