rs1555057838

Variant names:

• chr11-103179047-G-A
• rs1555057838
• NM_001080463.2:c.6161G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103179047-G-A
• chr11-103179047-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001080463.2(DYNC2H1):​c.6161G>A​(p.Cys2054Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2054S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.11
• 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), 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a region_of_interest AAA 2 (size 223) in uniprot entity DYHC2_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-103179047-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446688.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.6161G>A	p.Cys2054Tyr	missense_variant	Exon 39 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.6161G>A	p.Cys2054Tyr	missense_variant	Exon 39 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6161G>A	p.Cys2054Tyr	missense_variant	Exon 39 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.6161G>A	p.Cys2054Tyr	missense_variant	Exon 39 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459038 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725772

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110164

Other (OTH) AF: 0.00 AC: 0 AN: 60218

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;.;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PhyloP100		8.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D;.;.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.0020	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.93
MutPred		0.63		Gain of catalytic residue at I2053 (P = 0.0532);Gain of catalytic residue at I2053 (P = 0.0532);Gain of catalytic residue at I2053 (P = 0.0532);Gain of catalytic residue at I2053 (P = 0.0532);
MVP		0.60
MPC		0.49
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.84
Mutation Taster		=3/97	disease causing

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: rs1555057838; hg19: chr11-103049776;