rs181843638

Positions:

• chr5-55220703-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001190787.3(MCIDAS):​c.821G>A​(p.Gly274Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000606 in 1,536,024 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00054 (9 hom.)
• Consequence: MCIDAS NM_001190787.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.25

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055426955).
• BP6: Variant 5-55220703-C-T is Benign according to our data. Variant chr5-55220703-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00125 (190/152368) while in subpopulation AMR AF= 0.00797 (122/15312). AF 95% confidence interval is 0.00682. There are 1 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCIDAS	NM_001190787.3	c.821G>A	p.Gly274Glu	missense_variant	7/7	ENST00000513312.3	NP_001177716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCIDAS	ENST00000513312.3	c.821G>A	p.Gly274Glu	missense_variant	7/7	1	NM_001190787.3	ENSP00000426359	P1
MCIDAS	ENST00000513468.5	c.*285G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	5		ENSP00000422165

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 191 AN: 152250 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00804

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00386 AC: 519 AN: 134590 Hom.: 8 AF XY: 0.00271 AC XY: 199 AN XY: 73304

Gnomad AFR exome AF: 0.00140

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000286

Gnomad SAS exome AF: 0.000311

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.0000378

Gnomad OTH exome AF: 0.00169

GnomAD4 exome AF: 0.000536 AC: 741 AN: 1383656 Hom.: 9 Cov.: 35 AF XY: 0.000451 AC XY: 308 AN XY: 682756

Gnomad4 AFR exome AF: 0.000285

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000308

Gnomad4 SAS exome AF: 0.000328

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.0000454

Gnomad4 OTH exome AF: 0.000484

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152368 Hom.: 1 Cov.: 34 AF XY: 0.00136 AC XY: 101 AN XY: 74512

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000223 Hom.: 1

Bravo AF: 0.00205

ExAC AF: 0.000169 AC: 3

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Ciliary dyskinesia, primary, 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.22	T
Polyphen		0.66	P
Vest4		0.091
MVP		0.15
ClinPred		0.016	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs181843638; hg19: chr5-54516531;