11-103158787-A-G

Variant names:

• chr11-103158787-A-G
• rs688906
• NM_001080463.2:c.4238A>G

Variant summary

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

The NM_001080463.2(DYNC2H1):​c.4238A>G​(p.Lys1413Arg) variant causes a missense change. The variant allele was found at a frequency of 0.718 in 1,467,266 control chromosomes in the GnomAD database, including 381,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (35258 hom., cov: 32)
  • Exomes 𝑓: 0.72 (345999 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.90
• Publications: 43 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=1.3857141E-6).
• BP6: Variant 11-103158787-A-G is Benign according to our data. Variant chr11-103158787-A-G is described in ClinVar as Benign. ClinVar VariationId is 196009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

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.4238A>G	p.Lys1413Arg	missense	Exon 27 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.4238A>G	p.Lys1413Arg	missense	Exon 27 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.4238A>G	p.Lys1413Arg	missense	Exon 27 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.4238A>G	p.Lys1413Arg	missense	Exon 27 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+24368A>G		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102059 AN: 151798 Hom.: 35234 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.680

GnomAD2 exomes AF: 0.739 AC: 102345 AN: 138432 AF XY: 0.741

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.776

Gnomad EAS exome AF: 0.767

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.742

GnomAD4 exome AF: 0.723 AC: 950690 AN: 1315350 Hom.: 345999 Cov.: 32 AF XY: 0.723 AC XY: 470161 AN XY: 649918

African (AFR) AF: 0.478 AC: 13919 AN: 29092

American (AMR) AF: 0.795 AC: 23995 AN: 30166

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 18800 AN: 24128

East Asian (EAS) AF: 0.722 AC: 25160 AN: 34852

South Asian (SAS) AF: 0.720 AC: 50363 AN: 69960

European-Finnish (FIN) AF: 0.761 AC: 37145 AN: 48784

Middle Eastern (MID) AF: 0.700 AC: 3464 AN: 4946

European-Non Finnish (NFE) AF: 0.725 AC: 738394 AN: 1018354

Other (OTH) AF: 0.716 AC: 39450 AN: 55068

GnomAD4 genome AF: 0.672 AC: 102123 AN: 151916 Hom.: 35258 Cov.: 32 AF XY: 0.675 AC XY: 50131 AN XY: 74240

African (AFR) AF: 0.492 AC: 20369 AN: 41430

American (AMR) AF: 0.760 AC: 11600 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 2697 AN: 3468

East Asian (EAS) AF: 0.768 AC: 3965 AN: 5162

South Asian (SAS) AF: 0.721 AC: 3470 AN: 4812

European-Finnish (FIN) AF: 0.756 AC: 7950 AN: 10514

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.733 AC: 49797 AN: 67948

Other (OTH) AF: 0.680 AC: 1435 AN: 2110

Alfa AF: 0.717 Hom.: 172338

Bravo AF: 0.666

TwinsUK AF: 0.732 AC: 2715

ALSPAC AF: 0.724 AC: 2792

ESP6500AA AF: 0.513 AC: 1736

ESP6500EA AF: 0.742 AC: 5720

ExAC AF: 0.655 AC: 48854

Asia WGS AF: 0.702 AC: 2430 AN: 3458

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Asphyxiating thoracic dystrophy 3 (3)
-	-	2	Jeune thoracic dystrophy (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Benign	0.31	T
Sift4G	Benign	0.28	T
Polyphen		0.33	B
Vest4		0.049
MPC		0.093
ClinPred		0.018	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.48
Mutation Taster		=96/4	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: rs688906; hg19: chr11-103029516; COSMIC: COSV62088505;