chr11-103109635-T-C

Variant names:

• chr11-103109635-T-C
• rs1858012761
• NM_001080463.2:c.61T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001377.3(DYNC2H1):​c.61T>C​(p.Phe21Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. F21V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-103109635-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1031038.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13746166).

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.61T>C	p.Phe21Leu	missense	Exon 1 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.61T>C	p.Phe21Leu	missense	Exon 1 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.61T>C	p.Phe21Leu	missense	Exon 1 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.61T>C	p.Phe21Leu	missense	Exon 1 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.61T>C	p.Phe21Leu	missense	Exon 1 of 20	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.042
Sift	Benign	0.26	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.29		Gain of catalytic residue at F21 (P = 0.0555)
MVP		0.51
MPC		0.072
ClinPred		0.56	D
GERP RS		4.5
PromoterAI		-0.014	Neutral
Varity_R		0.23
gMVP		0.58
Mutation Taster		=73/27	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: rs1858012761; hg19: chr11-102980364;