Genetic Variant NM_181877.4:c.227C>T (chr15-84604154-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181877.4(ZSCAN2):c.227C>T(p.Ala76Val) 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 1,461,332 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. A76E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZSCAN2
NM_181877.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.87

Variant links:

Genes affected

ZSCAN2 (HGNC:20994): (zinc finger and SCAN domain containing 2) The protein encoded by this gene contains several copies of zinc finger motif, which is commonly found in transcriptional regulatory proteins. Studies in mice show that this gene is expressed during embryonic development, and specifically in the testis in adult mice, suggesting that it may play a role in regulating genes in germ cells. Alternative splicing of this gene results in several transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ZSCAN2 links:

ZSCAN2-AS1 (HGNC:56673): (ZSCAN2 antisense RNA 1)

ZSCAN2-AS1 links:

LOC105370947 (HGNC:):

LOC105370947 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSCAN2	NM_181877.4 link	c.227C>T	p.Ala76Val	missense_variant	Exon 2 of 3	ENST00000546148.6	NP_870992.2	Q7Z7L9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSCAN2	ENST00000546148.6 link	c.227C>T	p.Ala76Val	missense_variant	Exon 2 of 3	2	NM_181877.4	ENSP00000445451.1		Q7Z7L9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248910

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461332

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

.;T;T;.;.;.;T;.;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.033

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.95

D;.;.;D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;L;L;L;.;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.9

D;N;N;D;D;N;D;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0040

D;T;T;D;D;T;D;D;D

Sift4G

Uncertain

0.0080

D;T;T;D;D;T;D;D;D

Polyphen

0.32, 1.0, 1.0, 0.99, 0.96

.;B;B;D;D;.;D;D;D

Vest4

0.24, 0.24, 0.20, 0.19, 0.24, 0.29, 0.26, 0.27

MutPred

0.80

Gain of catalytic residue at A76 (P = 0.0509);Gain of catalytic residue at A76 (P = 0.0509);Gain of catalytic residue at A76 (P = 0.0509);Gain of catalytic residue at A76 (P = 0.0509);Gain of catalytic residue at A76 (P = 0.0509);Gain of catalytic residue at A76 (P = 0.0509);Gain of catalytic residue at A76 (P = 0.0509);Gain of catalytic residue at A76 (P = 0.0509);Gain of catalytic residue at A76 (P = 0.0509);

MVP

0.37

MPC

0.14

ClinPred

0.89

GERP RS

5.6

Varity_R

0.093

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over