rs189806840

Variant names:

• chr11-103155439-C-A
• rs189806840
• NM_001080463.2:c.3682C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103155439-C-A
• chr11-103155439-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001377.3(DYNC2H1):​c.3682C>A​(p.Leu1228Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,612,340 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1228L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:11 B:4
• Conservation: PhyloP100: 1.09
• Publications: 10 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008179843).
• BP6: Variant 11-103155439-C-A is Benign according to our data. Variant chr11-103155439-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238270.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0018 (274/151988) while in subpopulation AMR AF = 0.00505 (77/15258). AF 95% confidence interval is 0.00414. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.3682C>A	p.Leu1228Ile	missense	Exon 25 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.3682C>A	p.Leu1228Ile	missense	Exon 25 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.3682C>A	p.Leu1228Ile	missense	Exon 25 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.3682C>A	p.Leu1228Ile	missense	Exon 25 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+21020C>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 151872 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00162 AC: 402 AN: 247758 AF XY: 0.00169

Gnomad AFR exome AF: 0.000909

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00233 AC: 3398 AN: 1460352 Hom.: 6 Cov.: 33 AF XY: 0.00231 AC XY: 1678 AN XY: 726444

African (AFR) AF: 0.000628 AC: 21 AN: 33416

American (AMR) AF: 0.00343 AC: 153 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26096

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86022

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53380

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00273 AC: 3037 AN: 1111156

Other (OTH) AF: 0.00280 AC: 169 AN: 60316

GnomAD4 genome AF: 0.00180 AC: 274 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74286

African (AFR) AF: 0.000579 AC: 24 AN: 41464

American (AMR) AF: 0.00505 AC: 77 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 67960

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00215 Hom.: 1

Bravo AF: 0.00229

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000545 AC: 2

ESP6500EA AF: 0.00171 AC: 14

ExAC AF: 0.00136 AC: 164

EpiCase AF: 0.00284

EpiControl AF: 0.00256

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	1	not provided (7)
-	3	-	Asphyxiating thoracic dystrophy 3 (3)
2	-	1	Jeune thoracic dystrophy (3)
-	-	2	not specified (2)
-	1	-	Optic atrophy (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.53
MVP		0.62
MPC		0.36
ClinPred		0.023	T
GERP RS		-1.0
Varity_R		0.35
gMVP		0.38
Mutation Taster		=72/28	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: rs189806840; hg19: chr11-103026168;