21-26566321-C-A

Variant names:

• chr21-26566321-C-A
• rs1470722706
• NM_001320768.2:c.121G>T

Variant summary

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

The NM_001320768.2(CYYR1):​c.121G>T​(p.Asp41Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D41N) 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: 1.79
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.121G>T	p.Asp41Tyr	missense	Exon 2 of 4	NP_001307697.2	Q96J86-2
	CYYR1	NM_052954.5		c.121G>T	p.Asp41Tyr	missense	Exon 2 of 4	NP_443186.3	Q96J86-1
	CYYR1	NR_135472.2		n.467G>T		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYYR1	ENST00000652641.2	MANE Select	c.121G>T	p.Asp41Tyr	missense	Exon 2 of 4	ENSP00000498505.1	Q96J86-2
	CYYR1	ENST00000299340.9	TSL:1	c.121G>T	p.Asp41Tyr	missense	Exon 2 of 4	ENSP00000299340.4	Q96J86-1
	CYYR1	ENST00000400043.3	TSL:1	c.121G>T	p.Asp41Tyr	missense	Exon 2 of 4	ENSP00000382918.3	Q96J86-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461596 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727086

⚠️ 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: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ 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	0.31
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.029	D
Polyphen		0.60	P
Vest4		0.78
MutPred		0.44		Gain of catalytic residue at P45 (P = 0.0802)
MVP		0.33
MPC		0.13
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.71
gMVP		0.62
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs1470722706; hg19: chr21-27938640;