16-11276340-C-T

Variant names:

• chr16-11276340-C-T
• rs191601030
• NM_002762.4:c.31G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002762.4(PRM2):​c.31G>A​(p.Glu11Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,614,230 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: PRM2 NM_002762.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0850

Genes affected

PRM2 (HGNC:9448): (protamine 2) Protamines substitute for histones in the chromatin of sperm during the haploid phase of spermatogenesis, and are the major DNA-binding proteins in the nucleus of sperm in many vertebrates. They package the sperm DNA into a highly condensed complex in a volume less than 5% of a somatic cell nucleus. Many mammalian species have only one protamine (protamine 1); however, a few species, including human and mouse, have two. This gene encodes protamine 2, which is cleaved to give rise to a family of protamine 2 peptides. Alternatively spliced transcript variants have also been found for this gene. [provided by RefSeq, Sep 2015]

RMI2 (HGNC:28349): (RecQ mediated genome instability 2) RMI2 is a component of the BLM (RECQL3; MIM 604610) complex, which plays a role in homologous recombination-dependent DNA repair and is essential for genome stability (Xu et al., 2008 [PubMed 18923082]).[supplied by OMIM, Nov 2008]

LOC105371082 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063623786).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRM2	NM_002762.4	c.31G>A	p.Glu11Lys	missense_variant	Exon 1 of 2	ENST00000241808.9	NP_002753.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRM2	ENST00000241808.9	c.31G>A	p.Glu11Lys	missense_variant	Exon 1 of 2	1	NM_002762.4	ENSP00000241808.5

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00111 AC: 277 AN: 249322 Hom.: 2 AF XY: 0.000798 AC XY: 108 AN XY: 135288

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00785

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000217 AC: 317 AN: 1461878 Hom.: 2 Cov.: 36 AF XY: 0.000188 AC XY: 137 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00653

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: 0.00000989

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74498

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000467 Hom.: 0

Bravo AF: 0.000525

ExAC AF: 0.000841 AC: 102

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31G>A (p.E11K) alteration is located in exon 1 (coding exon 1) of the PRM2 gene. This alteration results from a G to A substitution at nucleotide position 31, causing the glutamic acid (E) at amino acid position 11 to be replaced by a lysine (K). 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	0.25
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.061
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.98	D;.
Vest4		0.37
MVP		0.33
MPC		0.42
ClinPred		0.11	T
GERP RS		1.4
Varity_R		0.41
gMVP		0.059

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

Publications

LitVar

Other links and lift over

dbSNP: rs191601030; hg19: chr16-11370197;