19-44175851-T-C

Variant names:

• chr19-44175851-T-C
• rs374027023
• NM_001032373.2:c.589T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001032373.2(ZNF226):​c.589T>C​(p.Cys197Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,613,528 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ZNF226 NM_001032373.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• Publications: 1 publications found

Genes affected

ZNF226 (HGNC:13019): (zinc finger protein 226) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06280121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF226	NM_001032373.2	c.589T>C	p.Cys197Arg	missense_variant	Exon 6 of 6	ENST00000337433.10	NP_001027545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF226	ENST00000337433.10	c.589T>C	p.Cys197Arg	missense_variant	Exon 6 of 6	1	NM_001032373.2	ENSP00000336719.5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000726 AC: 18 AN: 247976 AF XY: 0.0000668

Gnomad AFR exome AF: 0.0000654

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1461362 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 726930

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.000112 AC: 5 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53370

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

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1111762

Other (OTH) AF: 0.0000828 AC: 5 AN: 60358

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.000916 AC: 14 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000275 AC: 1

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.589T>C (p.C197R) alteration is located in exon 6 (coding exon 4) of the ZNF226 gene. This alteration results from a T to C substitution at nucleotide position 589, causing the cysteine (C) at amino acid position 197 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.033	T;T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.028	T;.;.
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;L;L
PhyloP100		1.5
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Benign	0.029
Sift	Benign	0.13	T;.;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.22
MVP		0.13
MPC		0.021
ClinPred		0.025	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.078
Mutation Taster		=97/3	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: rs374027023; hg19: chr19-44680004;