rs185737637

Variant names:

• chr5-55220668-C-T
• rs185737637
• NM_001190787.3:c.856G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-55220668-C-T
• chr5-55220668-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001190787.3(MCIDAS):​c.856G>A​(p.Glu286Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000411 in 1,536,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MCIDAS NM_001190787.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.69
• Publications: 0 publications found

Genes affected

MCIDAS (HGNC:40050): (multiciliate differentiation and DNA synthesis associated cell cycle protein) This gene encodes a member of the geminin family of proteins. The encoded nuclear protein is required for the generation of multiciliated cells in respiratory epithelium. Mutations in this gene cause a rare mucociliary clearance disorder associated with recurring respiratory infections in human patients, known as reduced generation of multiple motile cilia (RGMC). [provided by RefSeq, Sep 2016]

MCIDAS Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 42

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00573346).
• BP6: Variant 5-55220668-C-T is Benign according to our data. Variant chr5-55220668-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238623.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (337/152342) while in subpopulation AFR AF = 0.00777 (323/41582). AF 95% confidence interval is 0.00707. There are 0 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190787.3. 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
	MCIDAS	NM_001190787.3	MANE Select	c.856G>A	p.Glu286Lys	missense	Exon 7 of 7	NP_001177716.1	D6RGH6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCIDAS	ENST00000513312.3	TSL:1 MANE Select	c.856G>A	p.Glu286Lys	missense	Exon 7 of 7	ENSP00000426359.1	D6RGH6
	MCIDAS	ENST00000513468.5	TSL:5	n.*320G>A		non_coding_transcript_exon	Exon 7 of 7	ENSP00000422165.1	I6L8E2
	MCIDAS	ENST00000513468.5	TSL:5	n.*320G>A		3_prime_UTR	Exon 7 of 7	ENSP00000422165.1	I6L8E2

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 337 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00779

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000490 AC: 66 AN: 134582 AF XY: 0.000368

Gnomad AFR exome AF: 0.00823

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000946

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000212 AC: 294 AN: 1383756 Hom.: 0 Cov.: 30 AF XY: 0.000170 AC XY: 116 AN XY: 682822

African (AFR) AF: 0.00706 AC: 223 AN: 31594

American (AMR) AF: 0.000336 AC: 12 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33890

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.0000213 AC: 23 AN: 1078844

Other (OTH) AF: 0.000553 AC: 32 AN: 57898

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00221 AC XY: 165 AN XY: 74492

African (AFR) AF: 0.00777 AC: 323 AN: 41582

American (AMR) AF: 0.000718 AC: 11 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.00241

ExAC AF: 0.000290 AC: 5

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Ciliary dyskinesia, primary, 42 (1)
-	-	1	MCIDAS-related disorder (1)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.046
Sift	Uncertain	0.016	D
Sift4G	Benign	0.11	T
Polyphen		0.65	P
Vest4		0.23
MVP		0.085
ClinPred		0.048	T
GERP RS		4.8
Varity_R		0.23
gMVP		0.41
Mutation Taster		=69/31	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: rs185737637; hg19: chr5-54516496;