rs368058473

Variant names:

• chr11-103176381-G-C
• rs368058473
• NM_001080463.2:c.5821G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001377.3(DYNC2H1):​c.5821G>C​(p.Ala1941Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 1,592,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -0.112
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06887221).

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.5821G>C	p.Ala1941Pro	missense	Exon 37 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.5821G>C	p.Ala1941Pro	missense	Exon 37 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.5821G>C	p.Ala1941Pro	missense	Exon 37 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.5821G>C	p.Ala1941Pro	missense	Exon 37 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+41962G>C		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000590 AC: 13 AN: 220478 AF XY: 0.0000421

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000167

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000696

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.0000382 AC: 55 AN: 1440392 Hom.: 0 Cov.: 32 AF XY: 0.0000308 AC XY: 22 AN XY: 714490

African (AFR) AF: 0.0000307 AC: 1 AN: 32594

American (AMR) AF: 0.000240 AC: 10 AN: 41750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25716

East Asian (EAS) AF: 0.00 AC: 0 AN: 38760

South Asian (SAS) AF: 0.00 AC: 0 AN: 81010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000299 AC: 33 AN: 1102578

Other (OTH) AF: 0.000184 AC: 11 AN: 59648

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.000131 AC: 2 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.0000332 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	DYNC2H1-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Jeune thoracic dystrophy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.11
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.39
Sift	Benign	0.25	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.42
MVP		0.39
MPC		0.079
ClinPred		0.025	T
GERP RS		-3.2
Varity_R		0.24
gMVP		0.48
Mutation Taster		=60/40	polymorphism

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: rs368058473; hg19: chr11-103047110;