dbSNP rs757922501: DYNC2H1:p.Tyr3837Ser (chr11-103307827-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001377.3(DYNC2H1):c.11489A>C(p.Tyr3830Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000706 in 1,417,300 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. Y3830C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DYNC2H1
NM_001377.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.01

Publications

0 publications found

Variant links:

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

DYNC2H1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.11510A>C	p.Tyr3837Ser	missense_variant	Exon 79 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.11489A>C	p.Tyr3830Ser	missense_variant	Exon 78 of 89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DYNC2H1	ENST00000650373.2 link	c.11510A>C	p.Tyr3837Ser	missense_variant	Exon 79 of 90		NM_001080463.2	ENSP00000497174.1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.11489A>C	p.Tyr3830Ser	missense_variant	Exon 78 of 89	1	NM_001377.3	ENSP00000364887.2	Q8NCM8-1
DYNC2H1	ENST00000334267.11 link	c.2206-128116A>C		intron_variant	Intron 15 of 19	1		ENSP00000334021.7	Q8NCM8-3
DYNC2H1	ENST00000528670.5 link	n.668A>C		non_coding_transcript_exon_variant	Exon 6 of 17	5		ENSP00000433451.1	H0YDE0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.06e-7

AC:

AN:

1417300

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703672

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32494

American (AMR)

AF:

0.00

AC:

AN:

41640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25400

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38798

South Asian (SAS)

AF:

0.00

AC:

AN:

81526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081240

Other (OTH)

AF:

0.00

AC:

AN:

58648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;.;D

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M;.;.

PhyloP100

7.0

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.5

D;.;.;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

D;.;.;D

Sift4G

Uncertain

0.0050

D;.;.;D

Polyphen

0.87

P;P;P;P

Vest4

0.84

MutPred

0.69

Gain of disorder (P = 0.0076);Gain of disorder (P = 0.0076);.;.;

MVP

0.47

MPC

0.37

ClinPred

0.99

GERP RS

5.5

Varity_R

0.94

gMVP

0.75

Mutation Taster

=26/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over