11-103307730-A-T

Variant names:

• chr11-103307730-A-T
• rs764785064
• NM_001080463.2:c.11413A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377.3(DYNC2H1):​c.11392A>T​(p.Thr3798Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. T3798A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• 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), 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059859544).

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.11413A>T	p.Thr3805Ser	missense	Exon 79 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.11392A>T	p.Thr3798Ser	missense	Exon 78 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.11413A>T	p.Thr3805Ser	missense	Exon 79 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.11392A>T	p.Thr3798Ser	missense	Exon 78 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2206-128213A>T		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427238 Hom.: 0 Cov.: 28 AF XY: 0.00000141 AC XY: 1 AN XY: 707640

African (AFR) AF: 0.00 AC: 0 AN: 32736

American (AMR) AF: 0.00 AC: 0 AN: 41070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 38900

South Asian (SAS) AF: 0.00 AC: 0 AN: 78948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093704

Other (OTH) AF: 0.0000170 AC: 1 AN: 58970

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.62
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.53	N
PhyloP100		1.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.051
Sift	Benign	0.66	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.50		Gain of disorder (P = 0.0513)
MVP		0.12
MPC		0.057
ClinPred		0.13	T
GERP RS		3.1
Varity_R		0.066
gMVP		0.16
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs764785064; hg19: chr11-103178459;