rs969015057

Variant names:

• chr11-103200154-G-A
• rs969015057
• NM_001080463.2:c.8197G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103200154-G-A
• chr11-103200154-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001080463.2(DYNC2H1):​c.8197G>A​(p.Gly2733Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. 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. G2733C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-103200154-G-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446604.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.8197G>A	p.Gly2733Ser	missense_variant, splice_region_variant	Exon 50 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.8197G>A	p.Gly2733Ser	missense_variant, splice_region_variant	Exon 50 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.8197G>A	p.Gly2733Ser	missense_variant, splice_region_variant	Exon 50 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.8197G>A	p.Gly2733Ser	missense_variant, splice_region_variant	Exon 50 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391686 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 688402

African (AFR) AF: 0.00 AC: 0 AN: 31406

American (AMR) AF: 0.00 AC: 0 AN: 37222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 37178

South Asian (SAS) AF: 0.00 AC: 0 AN: 75698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070936

Other (OTH) AF: 0.00 AC: 0 AN: 57826

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;.;D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.3	M;M;M;M
PhyloP100		10
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.4	D;.;.;D
REVEL	Uncertain	0.50
Sift	Benign	0.060	T;.;.;T
Sift4G	Uncertain	0.057	T;.;.;T
Polyphen		1.0	D;D;D;D
Vest4		0.86
MutPred		0.57		Gain of phosphorylation at G2733 (P = 0.0427);Gain of phosphorylation at G2733 (P = 0.0427);Gain of phosphorylation at G2733 (P = 0.0427);Gain of phosphorylation at G2733 (P = 0.0427);
MVP		0.74
MPC		0.37
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.69
gMVP		0.78
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.53		Position offset: 0

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

Other links and lift over

dbSNP: rs969015057; hg19: chr11-103070883;