21-26468599-C-T

Variant names:

• chr21-26468599-C-T
• rs2064996373
• NM_001320768.2:c.370G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001320768.2(CYYR1):​c.370G>A​(p.Glu124Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E124Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYYR1 NM_001320768.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• Publications: 0 publications found

Genes affected

CYYR1 (HGNC:16274): (cysteine and tyrosine rich 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CYYR1-AS1 (HGNC:39560): (CYYR1 antisense RNA 1)

LOC107985474 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17300346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320768.2. 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
	CYYR1	NM_001320768.2	MANE Select	c.370G>A	p.Glu124Lys	missense	Exon 4 of 4	NP_001307697.2	Q96J86-2
	CYYR1	NM_052954.5		c.367G>A	p.Glu123Lys	missense	Exon 4 of 4	NP_443186.3	Q96J86-1
	CYYR1	NR_135472.2		n.883G>A		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYYR1	ENST00000652641.2	MANE Select	c.370G>A	p.Glu124Lys	missense	Exon 4 of 4	ENSP00000498505.1	Q96J86-2
	CYYR1	ENST00000299340.9	TSL:1	c.367G>A	p.Glu123Lys	missense	Exon 4 of 4	ENSP00000299340.4	Q96J86-1
	CYYR1-AS1	ENST00000357401.3	TSL:2	n.187-34983C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460466 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726418

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111208

Other (OTH) AF: 0.00 AC: 0 AN: 60346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.16
Sift	Benign	0.031	D
Sift4G	Benign	0.15	T
Polyphen		0.34	B
Vest4		0.42
MutPred		0.30		Gain of ubiquitination at E123 (P = 0.0066)
MVP		0.17
MPC		0.084
ClinPred		0.28	T
GERP RS		2.3
Varity_R		0.11
gMVP		0.52
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2064996373; hg19: chr21-27840918; COSMIC: COSV54830136;