dbSNP rs766433476: SREK1:p.Thr194Arg (chr5-66162418-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001077199.3(SREK1):c.581C>G(p.Thr194Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,524 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. T194M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SREK1
NM_001077199.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.39

Publications

2 publications found

Variant links:

Genes affected

SREK1 (HGNC:17882): (splicing regulatory glutamic acid and lysine rich protein 1) This gene encodes a member of a family of serine/arginine-rich (SR) splicing proteins containing RNA recognition motif (RRM) domains. The encoded protein interacts with other SR proteins to modulate splice site selection. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

SREK1 links:

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ACMG classification

Classification was made for transcript

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_001077199.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SREK1	NM_001077199.3	MANE Select	c.581C>G	p.Thr194Arg	missense	Exon 5 of 12	NP_001070667.1	Q8WXA9-2
SREK1	NM_001323529.2		c.581C>G	p.Thr194Arg	missense	Exon 5 of 12	NP_001310458.1
SREK1	NM_001323533.2		c.581C>G	p.Thr194Arg	missense	Exon 5 of 11	NP_001310462.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SREK1	ENST00000334121.11	TSL:2 MANE Select	c.581C>G	p.Thr194Arg	missense	Exon 5 of 12	ENSP00000334538.6	Q8WXA9-2
SREK1	ENST00000380918.7	TSL:1	c.233C>G	p.Thr78Arg	missense	Exon 6 of 13	ENSP00000370305.3	Q8WXA9-1
SREK1	ENST00000284041.7	TSL:1	n.514C>G		non_coding_transcript_exon	Exon 5 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251252

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461524

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111772

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.72

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

7.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.31

Sift

Benign

0.44

Sift4G

Benign

0.31

Polyphen

1.0

Vest4

0.71

MutPred

0.64

Gain of MoRF binding (P = 0.044)

MVP

0.53

MPC

1.9

ClinPred

0.76

GERP RS

5.5

Varity_R

0.29

gMVP

0.95

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over