rs17099969

Variant names:

• chr11-103121378-G-A
• rs17099969
• NM_001080463.2:c.1367G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103121378-G-A
• chr11-103121378-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377.3(DYNC2H1):​c.1367G>A​(p.Arg456Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,598,844 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (149 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (138 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.76
• 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), 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001755178).
• BP6: Variant 11-103121378-G-A is Benign according to our data. Variant chr11-103121378-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

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.1367G>A	p.Arg456Gln	missense	Exon 10 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.1367G>A	p.Arg456Gln	missense	Exon 10 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.1367G>A	p.Arg456Gln	missense	Exon 10 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.1367G>A	p.Arg456Gln	missense	Exon 10 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.1367G>A	p.Arg456Gln	missense	Exon 10 of 20	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3468 AN: 152026 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0790

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.00562 AC: 1297 AN: 230702 AF XY: 0.00429

Gnomad AFR exome AF: 0.0779

Gnomad AMR exome AF: 0.00372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00236 AC: 3408 AN: 1446700 Hom.: 138 Cov.: 30 AF XY: 0.00203 AC XY: 1458 AN XY: 718950

African (AFR) AF: 0.0859 AC: 2803 AN: 32644

American (AMR) AF: 0.00389 AC: 161 AN: 41440

Ashkenazi Jewish (ASJ) AF: 0.0000782 AC: 2 AN: 25590

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39496

South Asian (SAS) AF: 0.0000970 AC: 8 AN: 82438

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53032

Middle Eastern (MID) AF: 0.00334 AC: 19 AN: 5692

European-Non Finnish (NFE) AF: 0.0000795 AC: 88 AN: 1106638

Other (OTH) AF: 0.00542 AC: 324 AN: 59730

GnomAD4 genome AF: 0.0228 AC: 3471 AN: 152144 Hom.: 149 Cov.: 32 AF XY: 0.0217 AC XY: 1617 AN XY: 74372

African (AFR) AF: 0.0788 AC: 3269 AN: 41486

American (AMR) AF: 0.00857 AC: 131 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10570

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68026

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.00789 Hom.: 105

Bravo AF: 0.0262

ESP6500AA AF: 0.0760 AC: 274

ESP6500EA AF: 0.000491 AC: 4

ExAC AF: 0.00627 AC: 757

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	2	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	0.071
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		1.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.062
Sift	Benign	0.91	T
Sift4G	Benign	0.85	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.58
MPC		0.070
ClinPred		0.0076	T
GERP RS		5.4
Varity_R		0.033
gMVP		0.20
Mutation Taster		=91/9	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: rs17099969; hg19: chr11-102992107; COSMIC: COSV62101597;