5-55220785-G-A

Position:

• chr5-55220785-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001190787.3(MCIDAS):​c.739C>T​(p.Arg247Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,530,240 control chromosomes in the GnomAD database, including 36 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0058 (34 hom.)
• Consequence: MCIDAS NM_001190787.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0300

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00433442).
• BP6: Variant 5-55220785-G-A is Benign according to our data. Variant chr5-55220785-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238621.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00374 (569/152304) while in subpopulation NFE AF= 0.00653 (444/68028). AF 95% confidence interval is 0.00603. There are 2 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCIDAS	NM_001190787.3	c.739C>T	p.Arg247Trp	missense_variant	7/7	ENST00000513312.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCIDAS	ENST00000513312.3	c.739C>T	p.Arg247Trp	missense_variant	7/7	1	NM_001190787.3	P1
MCIDAS	ENST00000513468.5	c.*203C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152186 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00651

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00332 AC: 446 AN: 134210 Hom.: 1 AF XY: 0.00322 AC XY: 235 AN XY: 73076

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000936

Gnomad FIN exome AF: 0.000942

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00484

GnomAD4 exome AF: 0.00580 AC: 7994 AN: 1377936 Hom.: 34 Cov.: 35 AF XY: 0.00566 AC XY: 3842 AN XY: 678628

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00365

Gnomad4 ASJ exome AF: 0.0000797

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000872

Gnomad4 FIN exome AF: 0.000769

Gnomad4 NFE exome AF: 0.00699

Gnomad4 OTH exome AF: 0.00393

GnomAD4 genome AF: 0.00374 AC: 569 AN: 152304 Hom.: 2 Cov.: 34 AF XY: 0.00357 AC XY: 266 AN XY: 74476

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00386

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00856 AC: 33

ExAC AF: 0.00139 AC: 25

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Aug 10, 2015

- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Benign	0.060	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.18
MVP		0.25
ClinPred		0.032	T
GERP RS		2.0
Varity_R		0.074
gMVP		0.29

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: rs199825346; hg19: chr5-54516613; COSMIC: COSV72813269; COSMIC: COSV72813269;