22-36999842-C-T

Variant names:

• chr22-36999842-C-T
• rs749953160
• NM_001163857.2:c.632G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001163857.2(CIMIP4):​c.632G>A​(p.Arg211Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CIMIP4 NM_001163857.2 missense, splice_region
• Scores: Splicing: ADA: 0.00004353
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.36

Genes affected

CIMIP4 (HGNC:28568): (ciliary microtubule inner protein 4)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017512083).
• BP6: Variant 22-36999842-C-T is Benign according to our data. Variant chr22-36999842-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2462042.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIMIP4	NM_001163857.2	c.632G>A	p.Arg211Gln	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000381821.2	NP_001157329.1
CIMIP4	NM_178552.4	c.377G>A	p.Arg126Gln	missense_variant, splice_region_variant	Exon 4 of 6		NP_848647.1
CIMIP4	XM_011530165.3	c.632G>A	p.Arg211Gln	missense_variant, splice_region_variant	Exon 5 of 7		XP_011528467.1
CIMIP4	XM_011530166.2	c.377G>A	p.Arg126Gln	missense_variant, splice_region_variant	Exon 4 of 6		XP_011528468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEX33	ENST00000381821.2	c.632G>A	p.Arg211Gln	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_001163857.2	ENSP00000371243.1
TEX33	ENST00000402860.7	c.377G>A	p.Arg126Gln	missense_variant, splice_region_variant	Exon 4 of 6	1		ENSP00000385179.3
TEX33	ENST00000405091.6	c.632G>A	p.Arg211Gln	missense_variant, splice_region_variant	Exon 5 of 7	5		ENSP00000386118.2
TEX33	ENST00000442538.5	c.206G>A	p.Arg69Gln	missense_variant, splice_region_variant	Exon 2 of 4	3		ENSP00000406640.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152010 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249512 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460232 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152010 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74236

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 06, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.67
DEOGEN2	Benign	0.0021	.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.68	T;.;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.6	.;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.7	N;N;N
REVEL	Benign	0.067
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.18
MutPred		0.21		.;Loss of methylation at R211 (P = 0.0398);Loss of methylation at R211 (P = 0.0398);
MVP		0.014
MPC		0.033
ClinPred		0.047	T
GERP RS		-2.1
Varity_R		0.025
gMVP		0.022

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.010
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: rs749953160; hg19: chr22-37395883;