rs144717489

Variant names:

• chr11-103479194-G-C
• rs144717489
• NM_001080463.2:c.12886G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-103479194-G-C
• chr11-103479194-G-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001377.3(DYNC2H1):​c.12865G>C​(p.Gly4289Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,766 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.014 (189 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 8.25
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0082240105).
• BP6: Variant 11-103479194-G-C is Benign according to our data. Variant chr11-103479194-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 302131.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0108 (1649/152160) while in subpopulation NFE AF = 0.0156 (1060/67986). AF 95% confidence interval is 0.0148. There are 17 homozygotes in GnomAd4. There are 795 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.12886G>C	p.Gly4296Arg	missense	Exon 90 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.12865G>C	p.Gly4289Arg	missense	Exon 89 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.12886G>C	p.Gly4296Arg	missense	Exon 90 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.12865G>C	p.Gly4289Arg	missense	Exon 89 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2704G>C	p.Gly902Arg	missense	Exon 20 of 20	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1647 AN: 152042 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0127 AC: 3172 AN: 249120 AF XY: 0.0126

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00744

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0151

GnomAD4 exome AF: 0.0137 AC: 20055 AN: 1461606 Hom.: 189 Cov.: 30 AF XY: 0.0137 AC XY: 9967 AN XY: 727088

African (AFR) AF: 0.00233 AC: 78 AN: 33480

American (AMR) AF: 0.00798 AC: 357 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 1062 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00863 AC: 744 AN: 86252

European-Finnish (FIN) AF: 0.0176 AC: 938 AN: 53394

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.0144 AC: 15997 AN: 1111814

Other (OTH) AF: 0.0136 AC: 819 AN: 60366

GnomAD4 genome AF: 0.0108 AC: 1649 AN: 152160 Hom.: 17 Cov.: 32 AF XY: 0.0107 AC XY: 795 AN XY: 74360

African (AFR) AF: 0.00241 AC: 100 AN: 41516

American (AMR) AF: 0.00772 AC: 118 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0381 AC: 132 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4818

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1060 AN: 67986

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0164 Hom.: 21

Bravo AF: 0.0105

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00204 AC: 8

ESP6500EA AF: 0.0161 AC: 134

ExAC AF: 0.0129 AC: 1557

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0155

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Benign	0.64	T
Polyphen		0.047	B
Vest4		0.62
MutPred		0.46		Gain of solvent accessibility (P = 0.0037)
MPC		0.094
ClinPred		0.048	T
GERP RS		4.9
Varity_R		0.56
gMVP		0.65
Mutation Taster		=59/41	polymorphism (auto)

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: rs144717489; hg19: chr11-103349922; COSMIC: COSV62086990;