rs112218090

chr22-36762951-G-Achr22-36762951-G-C

Variant summary

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

The NM_001177701.3(IFT27):c.415C>T(p.Arg139Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,598,246 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0083 (25 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (14 hom.)
• Consequence: IFT27 NM_001177701.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.44

Genes affected

IFT27 (HGNC:18626): (intraflagellar transport 27) This gene encodes a GTP-binding protein that is a core component of the intraflagellar transport complex B. Characterization of the similar Chlamydomonas protein indicates a function in cell cycle control. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2012]

CACNG2-DT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053834617).
• BP6: Variant 22-36762951-G-A is Benign according to our data. Variant chr22-36762951-G-A is described in ClinVar as [Benign]. Clinvar id is 377288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36762951-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00829 (1263/152340) while in subpopulation AFR AF= 0.0278 (1157/41566). AF 95% confidence interval is 0.0265. There are 25 homozygotes in gnomad4. There are 598 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT27	NM_001177701.3	c.415C>T	p.Arg139Trp	missense_variant	6/7	ENST00000433985.7
CACNG2-DT	NR_134623.1	n.238-3393G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT27	ENST00000433985.7	c.415C>T	p.Arg139Trp	missense_variant	6/7	1	NM_001177701.3	P3

Frequencies

GnomAD3 genomes AF: 0.00824 AC: 1254 AN: 152222 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00213 AC: 520 AN: 244614 Hom.: 6 AF XY: 0.00155 AC XY: 205 AN XY: 132458

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000346

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000898 AC: 1299 AN: 1445906 Hom.: 14 Cov.: 30 AF XY: 0.000801 AC XY: 575 AN XY: 717444

Gnomad4 AFR exome AF: 0.0290

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000360

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00829 AC: 1263 AN: 152340 Hom.: 25 Cov.: 32 AF XY: 0.00803 AC XY: 598 AN XY: 74496

Gnomad4 AFR AF: 0.0278

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00264 Hom.: 3

Bravo AF: 0.00951

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0281 AC: 124

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T;T;D
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.010	D;D;.
Polyphen		0.97	D;D;.
Vest4		0.47
MVP		0.79
MPC		0.38
ClinPred		0.033	T
GERP RS		5.5
Varity_R		0.42
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs112218090; hg19: chr22-37158995;